Tumor Immunology of Ovarian Cancer

Ann Vankerckhoven
De tumor immunologie van eierstokkanker bestuderen met als doel het immuunsysteem als bondgenoot te gebruiken in nieuwe behandelingsstrategieën.

Het immuunsysteem als bondgenoot in de strijd tegen kanker

In dit thesisonderzoek werd de specifieke rol van het immuunsysteem in eierstokkanker nagegaan.

Een sluipende en succesvolle doder  

Eierstokkanker is een agressieve kanker die de belangrijkste oorzaak vormt van gynaecologische sterfte bij vrouwen. Eierstokkanker geeft weinig of geen klachten. Daardoor kan hij zich volledig verspreiden in de gehele buikholte voordat er nog maar de minste ongemakken ontstaan. Als er toch symptomen zouden zijn, zijn deze vaak niet-specifiek en niet ernstig genoeg om een dokter te contacteren: een opgeblazen gevoel, vage buikpijn en vermoeidheid. Wanneer eierstokkanker toch vastgesteld wordt, bevindt die zich dan ook vaak in een vergevorderd stadium. Momenteel bestaat de huidige behandeling uit een uitgebreide chirurgische ingreep waarbij alle kankergezwellen worden weggenomen. Dit wordt aangevuld met chemotherapie. De ganse behandeling duurt een zestal maanden. Helaas hervallen veel patiënten en vaak reageert de teruggekeerde tumor niet meer voldoende op chemotherapie. Minder dan 20% van de patiënten is nog in leven, vijf jaar na de diagnose. Er is dus een hoge nood aan nieuwe wapens om deze ziekte beter te kunnen gaan bestrijden. Daarin zien mijn collega’s en ikzelf het immuunsysteem als onze nieuwe bondgenoot.

Soldaten tegen kanker

Het immuunsysteem functioneert als een goed geoliede machine dat een leger aan witte bloedcellen gebruikt om het menselijke lichaam te verdedigen tegen allerlei indringers: bacteriën, virussen, maar ook kankercellen. Cellen van het immuunsysteem zijn in staat om kankercellen te herkennen en te vernietigen. Op deze manier beschermt het immuunsysteem ons, net zoals dat het geval is wanneer we een verkoudheid hebben. Immunotherapieën, die dit immuunsysteem manipuleren om zo kanker te kunnen bestrijden, kennen de laatste jaren een enorme opmars. Voor sommige kankers, zoals bijvoorbeeld huidkanker, boeken deze immunotherapieën grote successen. Daarom worden deze succesvolle – maar ook dure –   immunotherapieën geopperd als behandeling voor bijna alle kankers in klinische studies. Echter, voor heel wat soorten kanker, waaronder eierstokkanker, blijft het succesverhaal afwezig. Een mogelijke verklaring voor dit falen ligt vermoedelijk in het feit dat het gedrag van het immuunsysteem (dat men probeert te veranderen met immunotherapie) anders en specifiek is voor elke kanker. En met dat gegeven wordt op dit moment niet echt rekening gehouden in de lancering van immunotherapie.

Op zoek naar een strategisch aanvalsplan

Welke immuuncellen zijn dan belangrijk bij eierstokkanker? Hoe werken ze? Hoe en met welke wapens kunnen we ze beïnvloeden en zo de mensen langer laten leven? Omdat de mens moeilijk als proefpersoon kan gebruikt worden, wordt het onderzoek uitgevoerd op muizen met eierstokkanker. Deze muis ontwikkelt eierstokkanker net zoals een mens. In een allereerste experiment gingen we na of een speciaal type immuun cel, meer bepaald de “myeloid afgeleide onderdrukkende cellen (myeloid derived suppressor cells)”, kortweg MDSC, een rol speelt in eierstokkanker. Deze cel is nog niet zo lang gekend bij onderzoekers. MDSC zijn in vele opzichten speciale cellen. Ze zijn onvolwassen en jong van aspect (immatuur), waardoor ze - in tegenstelling tot hun volwassen equivalenten - immunosuppressieve capaciteiten bezitten. Dit betekent bijvoorbeeld dat ze andere (volwassen) immuun cellen, bijvoorbeeld een T-cel, kunnen tegenhouden wanneer deze een kankercel zouden willen aanvallen en elimineren. Ze gaan er eigenlijk voor zorgen dat de tumor meer kansen krijgt om zich te ontwikkelen. In deze thesis konden wij vaststellen dat het aantal MDSC steeg naarmate eierstokkanker zich verder ontwikkelde (meer uitzaaiingen).  Onze interesse was gewekt. We gingen een stapje verder en konden aantonen dat in een kweekschaaltje die bewuste MDSC effectief in staat waren de goede T-cellen volledig te verlammen. De T-cellen konden niet meer delen en meer nog, ze moesten in aantal inboeten en werden vervangen door regulerende T-cellen, waarvan ook geweten is dat ze de groei van de kanker bevorderen. Om zeker te zijn van de belangrijke rol van MDSC in eierstokkanker gebruikte we ook nog een genetisch gemanipuleerde muis die geen MDSC heeft. Hier zagen we duidelijk dat muizen mét MDSC veel sneller ziek werden van hun kanker dan de muizen zonder MDSC.

Voldoende bewijs dus voor ons dat MDSC een belangrijke invloed uitoefent bij de ontwikkeling van eierstokkanker, maar hoe kunnen we deze nu tegen houden? Dit onderzoek is nog in volle ontwikkeling maar we hebben reeds de effecten van de meest gebruikte chemotherapieën bij eierstokkanker bekeken. Carboplatinum-Paclitaxel (onze nummer één keuze van chemotherapie bij eierstokkanker) kwam als winnaar uit de bus met een positief effect op het totale immuunsysteem, echter, zonder duidelijke vermindering in MDSC.

Deze thesis heeft belangrijke informatie toegevoegd aan de immunologische puzzel. MDSC hebben zeker een sleutelrol. Maar ze aanvallen is nog een andere zaak. We mogen ook niet vergeten dat deze MDSC niet alleen zijn in ons lichaam en dat therapie gericht tegen hen ongetwijfeld effecten zal hebben op andere cellen. Om immunotherapieën zinvol te kunnen gebruiken als anti-kanker middelen hebben we duidelijk nog meer inzichten nodig. Meer dan waarschijnlijk ligt het antwoord voor een succesvolle behandeling in een combinatie van verschillende soorten therapieën, op het juiste moment, in de juiste volgorde. Daarom dat mijn collega’s en ikzelf dagelijks onderzoek blijven doen om dit mysterie verder te ontrafelen, zodat we patiënten uiteindelijk een succesvolle nieuwe behandeling kunnen geven.  

Bibliografie

1.  Globocan. [Online] Available from: http://globocan.iarc.fr/old/summary_table_pop_prev.asp?selection=224900… w=1&sort=0&submit= Execute

2.  Coburn SB, Bray F, Sherman ME, Trabert B. International patterns and trends in ovarian cancer incidence, overall and by histologic subtype. International Journal of Cancer. [Online] 2017;140(11): 2451–2460. Available from: doi:10.1002/ijc.30676

3.  La Vecchia C. Ovarian cancer: epidemiology and risk factors. European Journal of Cancer Prevention. [Online] 2017;26(1): 55–62. Available from: doi:10.1038/nrdp.2016.62

4.  Maxwell Parkin D, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. International Journal of Cancer. [Online] 2001;94(2): 153–156. Available from: doi:10.1002/ijc.1440

5.  Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. [Online] 2016;66(1): 7–30. Available from: doi:10.3322/caac.21332.

6.  HEINTZ A, ODICINO F, MAISONNEUVE P, QUINN M, BENEDET J, CREASMAN W, et al. Carcinoma of the Ovary. International Journal of Gynecology and Obstetrics. [Online] 2006;95(SUPPL. 1): 184–190. Available from: doi:10.1016/S0020-7292(06)60033-7

7.  Rosendahl M, Høgdall CK, Mosgaard BJ. Restaging and Survival Analysis of 4036 Ovarian Cancer Patients According to the 2013 FIGO Classification for Ovarian, Fallopian Tube, and Primary Peritoneal Cancer. International Journal of Gynecological Cancer. [Online] 2016;26(4): 680–687. Available from: doi:10.1097/IGC.0000000000000675

8.  Prat J. Abridged republication of FIGO’s staging classification for cancer of the ovary, fallopian tube, and peritoneum. Cancer. [Online] International Federation of Gynecology and Obstetrics; 2015;121(19): 3452–3454. Available from: doi:10.1002/cncr.29524

9.  Lengyel E. Ovarian Cancer Development and Metastasis. The American Journal of Pathology. [Online] 2010;177(3): 1053–1064. Available from: doi:10.2353/ajpath.2010.100105 [Accessed: 21st August 2017]

10.  Eisenkop SM, Spirtos NM. The clinical significance of occult macroscopically positive retroperitoneal nodes in patients with epithelial ovarian cancer. Gynecologic oncology. [Online] 2001;82(1): 143–149. Available from: doi:10.1006/gyno.2001.6232 [Accessed: 5th September 2017]

11.  Parazzini F, Valsecchi G, Bolis G, Guarnerio P, Reina S, Polverino G, et al. Pelvic and paraortic lymph nodal status in advanced ovarian cancer and survival. Gynecologic Oncology. [Online] 1999;74(1): 7–11. Available from: doi:10.1006/gyno.1999.5397 [Accessed: 5th September 2017]

12.  Baert T, Storme N, Van Nieuwenhuysen E, Uyttebroeck A, Van Damme N, Vergote I, et al. Ovarian cancer in children and adolescents: A rare disease that needs more attention. [Online] Maturitas. 2016. p. 3–8. Available from: doi:10.1016/j.maturitas.2016.03.003 [Accessed: 24th August 2017]

13.  Vang R, Shih I-M, Kurman RJ. Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Advances in anatomic pathology. [Online] 2009;16(5): 267–282. Available from: doi:10.1097/PAP.0b013e3181b4fffa [Accessed: 10th October 2017]

14.  Bast RC, Hennessy B, Mills GB. The biology of ovarian cancer: new opportunities for translation. Nature Reviews Cancer. [Online] 2009;9(6): 415–428. Available from: doi:10.1038/nrc2644 [Accessed: 29th August 2017]

15.  Rojas V, Hirshfield KM, Ganesan S, Rodriguez-Rodriguez L. Molecular characterization of epithelial ovarian cancer: Implications for diagnosis and treatment. [Online] International Journal of Molecular Sciences. Multidisciplinary Digital Publishing Institute (MDPI); 2016. Available from: doi:10.3390/ijms17122113 [Accessed: 23rd August 2017]

16.  Network CGAR, Kandoth C, Schultz N, Cherniack A, Akbani R, Liu Y, et al. Integrated Genomic Characterization of Endometrial Carcinoma. Nature. [Online] 2013;497(7447): 67–73. Available from: doi:10.1038/nature12113.Integrated [Accessed: 30th August 2017]

17.  Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, Sharma R, et al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. Journal of Pathology. [Online] 2010;221(1): 49–56. Available from: doi:10.1002/path.2696 [Accessed: 29th August 2017]

18.  Karnezis AN, Cho KR, Gilks CB, Pearce CL, Huntsman DG. The disparate origins of ovarian cancers: pathogenesis and prevention strategies. Nature Reviews Cancer. [Online] Nature Publishing Group; 2016;17(1): 65–74. Available from: doi:10.1038/nrc.2016.113

19.  The Cancer Genome Atlas Network. Integrated Genomic Analyses of Ovarian Carcinoma. Nature. [Online] 2011;474(7353): 609–615. Available from: doi:10.1038/nature10166.Integrated [Accessed: 31st August 2017]

20.  Chetrit A, Hirsh-Yechezkel G, Ben-David Y, Lubin F, Friedman E, Sadetzki S. Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: The National Israeli Study of Ovarian Cancer. Journal of Clinical Oncology. [Online] 2008;26(1): 20–25. Available from: doi:10.1200/JCO.2007.11.6905 [Accessed: 31st August 2017]

21.  Cooke SL, Brenton JD. Evolution of platinum resistance in high-grade serous ovarian cancer. [Online] The Lancet Oncology. 2011. p. 1169–1174. Available from: doi:10.1016/S14702045(11)70123-1 [Accessed: 29th August 2017]

22.  Alkema NG, Wisman GBA, van der Zee AG, van Vugt MATM, de Jong S. Studying platinum sensitivity and resistance in high-grade serous ovarian cancer: different models for different questions. Drug Resistance Updates. [Online] 2015;24: 55–69. Available from: doi:10.1016/j.drup.2015.11.005 [Accessed: 29th August 2017]

23.  Sherwood LM, Parris EE, Folkman J. Tumor Angiogenesis: Therapeutic Implications. New England Journal of Medicine. [Online] Massachusetts Medical Society; 1971;285(21): 1182– 1186. Available from: doi:10.1056/NEJM197111182852108 [Accessed: 23rd October 2017]

24.  Jain RK. Antiangiogenesis Strategies Revisited: From Starving Tumors to Alleviating Hypoxia. Cancer Cell. [Online] 2014;26(5): 605–622. Available from: doi:10.1016/j.ccell.2014.10.006 [Accessed: 23rd October 2017]

25.  Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. The Journal of Experimental Medicine. [Online] 2014;211(5): 781–790. Available from: doi:10.1084/jem.20131916 [Accessed: 3rd October 2017]

26.  Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. Journal of Clinical Oncology. [Online] European Cancer Congress; 2014;32(13): 1302–1308. Available from: doi:10.1200/JCO.2013.51.4489 [Accessed: 31st August 2017]

27.  Mullen P, Cameron DA, Hasmann M, Smyth JF, Langdon SP. Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling. Mol Cancer Ther. [Online] 2007;6(1): 93–100. Available from: doi:10.1158/1535-7163.MCT-06-0401 [Accessed: 31st August 2017]

28.  González-Martín A, Pautier P, Mahner S, Rau J, Colombo N, Ottevanger P, et al. Pertuzumab Plus Chemotherapy for Platinum-Resistant Ovarian Cancer: Safety Run-in Results of the PENELOPE Trial. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. [Online] 2016;26(5): 898–905. Available from: doi:10.1097/IGC.0000000000000695 [Accessed: 31st August 2017]

29.  Ruscio A Di, Ebralidze AK, Benoukraf T, Goff LA, Terragni J, Figueroa ME, et al. Epidermal Growth Factor Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First-Line Platinum-Based Chemotherapy. Target Oncology. [Online] 2015;503(7476): 371–376. Available from: doi:10.1038/nature12598.DNMT1-interacting

30.  Vergote IB, Jimeno A, Joly F, Katsaros D, Coens C, Despierre E, et al. Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based chemotherapy for ovarian carcinoma: A European Organisation for Research and Treatment of Cancer-Gynaecological Ca. Journal of Clinical Oncology. [Online] 2014;32(4): 320–326. Available from: doi:10.1200/JCO.2013.50.5669 [Accessed: 31st August2017]

31.  Gottschalk N, Kimmig R, Lang S, Singh M, Brandau S. Anti-epidermal growth factor receptor (EGFR) antibodies overcome resistance of ovarian cancer cells to targeted therapy and natural cytotoxicity. International Journal of Molecular Sciences. [Online] 2012;13(9): 12000–12016. Available from: doi:10.3390/ijms130912000 [Accessed: 31st August 2017]

32.  Gui T, Shen K. The epidermal growth factor receptor as a therapeutic target in epithelial ovarian cancer. Cancer Epidemiology. [Online] Elsevier Ltd; 2012;36(5): 490–496. Available from: doi:10.1016/j.canep.2012.06.005

33.  Steffensen KD, Waldstrøm M, Pallisgård N, Lund B, Bergfeldt K, Wihl J, et al. Panitumumab and pegylated liposomal doxorubicin in platinum-resistant epithelial ovarian cancer with KRAS wildtype: the PaLiDo study, a phase II nonrandomized multicenter study. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. [Online] 2013;23(1): 73–80. Available from: doi:10.1097/IGC.0b013e3182775fae

34.  Murphy M, Stordal B. Erlotinib or gefitinib for the treatment of relapsed platinum pretreated nonsmall cell lung cancer and ovarian cancer: A systematic review. [Online] Drug Resistance Updates. 2011. p. 177–190. Available from: doi:10.1016/j.drup.2011.02.004 [Accessed: 31st August 2017]

35.  Parkes EE, Kennedy RD. Clinical application of poly(ADP-ribose) polymerase inhibitors in highgrade serous ovarian cancer. Oncologist. [Online] 2016;21(5): 586–593. Available from: doi:10.1634/theoncologist.2015-0438 [Accessed: 31st August 2017]

36.  Jubin T, Kadam A, Jariwala M, Bhatt S, Sutariya S, Gani AR, et al. The PARP family: insights into functional aspects of poly (ADP-ribose) polymerase-1 in cell growth and survival. [Online] Cell Proliferation. 2016. p. 421–437. Available from: doi:10.1111/cpr.12268 [Accessed: 31st August 2017]

37.  Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. The New England journal of medicine. [Online] 2016; NEJMoa1611310. Available from: doi:10.1056/NEJMoa1611310

38.  Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. [Online] 2017;390(10106): 1949–1961. Available from: doi:10.1016/S0140-6736(17)32440-6

39.  Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. The Lancet Oncology. [Online] 2017;18(9): 1274–1284. Available from: doi:10.1016/S1470-2045(17)30469-2

40.  Domchek SM, Aghajanian C, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecologic Oncology. [Online] Elsevier Inc.; 2016;140(2): 199–203. Available from: doi:10.1016/j.ygyno.2015.12.020

41.  Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. The Lancet Oncology. [Online] Elsevier Ltd; 2017;18(1): 75–87. Available from: doi:10.1016/S1470-2045(16)30559-9

42.  Owen J, Punt J, Stranford S. Kuby Immunology. [Online] W.H.Freeman & Co Ltd; 2013. Available from: doi:10.1017/CBO9781107415324.004

43.  Boon T, Coulie PG, Van den Eynde B. Tumor antigens recognized by T cells. Immunology Today. [Online] Elsevier; 1997;18(6): 267–268. Available from: doi:10.1016/S0167-5699(97)80020-5 [Accessed: 20th September 2017]

44.  Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nature Reviews Cancer. [Online] 2014;14(2): 135–146. Available from: doi:10.1038/nrc3670 [Accessed: 12th September 2017]

45.  Strasser A, Jost PJ, Nagata S. The Many Roles of FAS Receptor Signaling in the Immune System. [Online] Immunity. 2009. p. 180–192. Available from: doi:10.1016/j.immuni.2009.01.001 [Accessed: 26th November 2017]

46.  Ibrahim EM, Al-Foheidi ME, Al-Mansour MM, Kazkaz GA. The prognostic value of tumorinfiltrating lymphocytes in triple-negative breast cancer: a meta-analysis. [Online] Breast Cancer Research and Treatment. 2014. p. 467–476. Available from: doi:10.1007/s10549-014-3185-2 [Accessed: 12th September 2017]

47.  Geng Y, Shao Y, He W, Hu W, Xu Y, Chen J, et al. Prognostic role of tumor-infiltrating lymphocytes in lung cancer: A meta-analysis. Cellular Physiology and Biochemistry. [Online] 2015;37(4): 1560–1571. Available from: doi:10.1159/000438523 [Accessed: 12th September 2017]

48.  Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+ tumorinfiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proceedings of the National Academy of Sciences. [Online] 2005;102(51): 18538–18543. Available from: doi:10.1073/pnas.0509182102 [Accessed: 21st November 2017]

49.  Galon J. Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome. Science. [Online] 2006;313(5795): 1960–1964. Available from: doi:10.1126/science.1229223

50.  Clemente CG, Mihm MC, Bufalino R, Zurrida S, Collini P, Cascinelli N. Prognostic value of tumorinfiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. [Online] 1996;77: 1303–1310. Available from: doi:10.1002/(SICI)10970142(19960401)77:7<1303::AID-CNCR12>3.0.CO;2-5

51.  Schumacher K, Haensch W, Röefzaad C, Ro C, Schlag PM. Prognostic Significance of Activated CD8 + T Cell Infiltrations within Esophageal Carcinomas Prognostic Significance of Activated CD8 ؉ T Cell Infiltrations within Esophageal Carcinomas. CANCER RESEARCH. [Online] 2001;61: 3932–3936. Available from: http://cancerres.aacrjournals.org/content/canres/61/10/3932.full.pdf [Accessed: 21st September 2017]

52.  Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer. The New England journal of medicine. [Online] 2003;3483348: 203–213. Available from: http://www.nejm.org/doi/pdf/10.1056/NEJMoa020177 [Accessed: 21st September 2017]

53.  Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Medicine. [Online] 2004;10(9): 942–949. Available from: doi:10.1038/nm1093

54.  Miyara M, Sakaguchi S. Natural regulatory T cells: mechanisms of suppression. [Online] Trends in Molecular Medicine. 2007. p. 108–116. Available from: doi:10.1016/j.molmed.2007.01.003 [Accessed: 28th November 2017]

55.  Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nature Reviews Immunology. [Online] 2006;6(4): 295–307. Available from: doi:10.1038/nri1806

56.  Lotze MT, Zeh HJ, Rubartelli A, Sparvero LJ, Amoscato AA, Washburn NR, et al. The grateful dead: Damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunological Reviews. [Online] 2007;220(1): 60–81. Available from: doi:10.1111/j.1600-065X.2007.00579.x [Accessed: 6th November 2017]

57.  Berraondo P, Minute L, Ajona D, Corrales L, Melero I, Pio R. Innate immune mediators in cancer: between defense and resistance. Immunological Reviews. [Online] 2016;274(1): 290–306. Available from: doi:10.1111/imr.12464

58.  Tran Janco JM, Lamichhane P, Karyampudi L, Knutson KL. Tumor-Infiltrating Dendritic Cells in Cancer Pathogenesis. The Journal of Immunology. [Online] 2015;194(7): 2985–2991. Available from: doi:10.4049/jimmunol.1403134 [Accessed: 2nd October 2017]

59.  Ledesma E, Martínez I, Córdova Y, Rodríguez-Sosa M, Monroy A, Mora L, et al. Interleukin-1 beta (IL-1β) induces tumor necrosis factor alpha (TNF-α) expression on mouse myeloid multipotent cell line 32D cl3 and inhibits their proliferation. Cytokine. [Online] Academic Press; 2004;26(2): 66–72. Available from: doi:10.1016/j.cyto.2003.12.009 [Accessed: 29th October 2017]

60.  Tesone AJ, Svoronos N, Allegrezza MJ, Conejo-Garcia JR. Pathological mobilization and activities of dendritic cells in tumor-bearing hosts: Challenges and opportunities for immunotherapy of cancer. [Online] Frontiers in Immunology. 2013. Available from: doi:10.3389/fimmu.2013.00435 [Accessed: 6th November 2017]

61.  Krempski J, Karyampudi L, Behrens MD, Erskine CL, Hartmann L, Dong H, et al. TumorInfiltrating Programmed Death Receptor-1+ Dendritic Cells Mediate Immune Suppression in Ovarian Cancer. The Journal of Immunology. [Online] 2011;186(12): 6905–6913. Available from: doi:10.4049/jimmunol.1100274 [Accessed: 6th November 2017]

62.  Harimoto H, Shimizu M, Nakagawa Y, Nakatsuka K, Wakabayashi A, Sakamoto C, et al. Erratum: Inactivation of tumor-specific CD8 + CTLs by tumor-infiltrating tolerogenic dendritic cells (Immunology and Cell Biology (2013) 91:665 Doi:10.1038/icb.2013.82). Immunology and Cell Biology. [Online] 2013;91(10): 665. Available from: doi:10.1038/icb.2013.82

63.  Hargadon KM. Tumor-altered dendritic cell function: Implications for anti-tumor immunity. [Online] Frontiers in Immunology. 2013. Available from: doi:10.3389/fimmu.2013.00192 [Accessed: 6th November 2017]

64.  Engström A, Erlandsson A, Delbro D, Wijkander J. Conditioned media from macrophages of M1, but not M2 phenotype, inhibit the proliferation of the colon cancer cell lines HT-29 and CACO-2. International Journal of Oncology. [Online] 2014;44(2): 385–392. Available from: doi:10.3892/ijo.2013.2203

65.  Yuan A, Hsiao Y-J, Chen H-Y, Chen H-W, Ho C-C, Chen Y-Y, et al. Opposite Effects of M1 and M2 Macrophage Subtypes on Lung Cancer Progression. Scientific Reports. [Online] 2015;5(1): 14273. Available from: doi:10.1038/srep14273 [Accessed: 20th September 2017]

66.  Sousa S, Brion R, Lintunen M, Kronqvist P, Sandholm J, Mönkkönen J, et al. Human breast cancer cells educate macrophages toward the M2 activation status. Breast Cancer Research. [Online] 2015;17(1): 101. Available from: doi:10.1186/s13058-015-0621-0 [Accessed: 20th September 2017]

67.  Zhang M, He Y, Sun X, Li Q, Wang W, Zhao A, et al. A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. Journal of ovarian research. [Online] 2014;7(1): 19. Available from: doi:10.1186/1757-2215-7-19 [Accessed: 19th September 2017]

68.  Edin S, Wikberg ML, Dahlin AM, Rutegård J, Öberg Å, Oldenborg PA, et al. The Distribution of Macrophages with a M1 or M2 Phenotype in Relation to Prognosis and the Molecular Characteristics of Colorectal Cancer. PLoS ONE. [Online] 2012;7(10). Available from: doi:10.1371/journal.pone.0047045 [Accessed: 20th September 2017]

69.  Pollard JW. Opinion: Tumour-educated macrophages promote tumour progression and metastasis. Nature Reviews Cancer. [Online] 2004;4(1): 71–78. Available from:doi:10.1038/nrc1256

70.  Xiong H, Zhu C, Li F, Hegazi R, He K, Babyatsky M, et al. Inhibition of Interleukin-12 p40 Transcription and NF-κB Activation by Nitric Oxide in Murine Macrophages and Dendritic Cells. Journal of Biological Chemistry. [Online] 2004;279(11): 10776–10783. Available from: doi:10.1074/jbc.M313416200 [Accessed: 29th September 2017]

71.  Garrido F, Ruiz-Cabello F, Cabrera T, Pérez-Villar JJ, López-Botet M, Duggan-Keen M, et al. Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. [Online] Immunology Today. 1997. p. 89–95. Available from: doi:10.1016/S01675699(96)10075-X [Accessed: 18th September 2017]

72.  Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nature Reviews Immunology. [Online] 2001;1(1): 41–49. Available from: doi:10.1038/35095564

73.  Condamine T, Mastio J, Gabrilovich DI. Transcriptional regulation of myeloid-derived suppressor cells. Journal of Leukocyte Biology. [Online] 2015;98(6): 913–922. Available from: doi:10.1189/jlb.4RI0515-204R

74.  Voehringer D. Protective and pathological roles of mast cells and basophils. Nature Reviews Immunology. [Online] 2013;13(5): 362–375. Available from: doi:10.1038/nri3427 [Accessed: 27th September 2017]

75.  O’Donnell JA, Kennedy CL, Pellegrini M, Nowell CJ, Zhang J-G, O’Reilly LA, et al. Fas regulates neutrophil lifespan during viral and bacterial infection. Journal of Leukocyte Biology. [Online] 2015;97(2): 321–326. Available from: doi:10.1189/jlb.3AB1113-594RR [Accessed: 27th September 2017]

76.  Wang A. Formylpeptide receptors mediate rapid neutrophil mobilization to accelerate wound healing. PloS one. [Online] 2014;9(6): e90613. Available from: doi:10.1371/journal.pone.0090613 [Accessed: 2nd October 2017]

77.  Deryugina EI, Zajac E, Juncker-Jensen A, Kupriyanova TA, Welter L, Quigley JP. TissueInfiltrating Neutrophils Constitute the Major In Vivo Source of Angiogenesis-Inducing MMP-9 in the Tumor Microenvironment. Neoplasia. [Online] 2014;16(10): 771–788. Available from: doi:10.1016/j.neo.2014.08.013 [Accessed: 2nd October 2017]

78.  Pruijt JFM, Verzaal P, van Os R, de Kruijf E-JFM, van Schie MLJ, Mantovani A, et al. Neutrophils are indispensable for hematopoietic stem cell mobilization induced by interleukin-8 in mice. Proceedings of the National Academy of Sciences of the United States of America. [Online] 2002;99(9): 6228–6233. Available from: doi:10.1073/pnas.092112999 [Accessed: 2nd October 2017]

79.  Brandau S, Dumitru CA, Lang S. Protumor and antitumor functions of neutrophil granulocytes. [Online] Seminars in Immunopathology. 2013. p. 163–176. Available from: doi:10.1007/s00281012-0344-6 [Accessed: 27th September 2017]

80.  Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews Immunology. [Online] 2009;9(3): 162–174. Available from: doi:10.1038/nri2506 [Accessed: 21st August 2017]

81.  Burnet M. Cancer-a Biological Approach Iii. Viruses Associated With Neoplastic Conditions. British Medical Journal. [Online] 1957;1: 841–847. Available from: doi:10.1136/bmj.1.5023.841 [Accessed: 20th September 2017]

82.  Thomas L. On immunosurveillance in human cancer. Yale Journal of Biology and Medicine. [Online] 1982;55(3–4): 329–333. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596448/pdf/yjbm00110-0164… [Accessed: 20th September 2017]

83.  Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunology. [Online] 2002;3(11): 991–998. Available from: doi:10.1038/ni1102-991 [Accessed: 4th September 2017]

84.  Oettinger MA, Schatz DG, Gorka C, Baltimore D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. [Online] 1990;248(4962): 1517–1523. Available from: doi:10.1126/science.2360047 [Accessed: 11th September 2017]

85.  Shinkai Y, Rathbun 0Gary, Lam KP, Oltz EM, Stewart V, Mendelsohn M, et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. [Online] 1992;68(5): 855–867. Available from: doi:10.1016/0092-8674(92)90029-C

86.  Dunn GP, Old LJ, Schreiber RD. The Three Es of Cancer Immunoediting. Annual Review of Immunology. [Online] 2004;22(1): 329–360. Available from: doi:10.1146/annurev.immunol.22.012703.104803 [Accessed: 6th September 2017]

87.  Erdman SE, Poutahidis T, Tomczak M, Rogers AB, Cormier K, Plank B, et al. CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. Am J Pathol. [Online] 2003;162(2): 691–702. Available from: doi:10.1016/S0002-9440(10)63863-1 [Accessed: 6th September 2017]

88.  Fujii H, Arakawa A, Utsumi D, Sumiyoshi S, Yamamoto Y, Kitoh A, et al. CD8+tumor-infiltrating lymphocytes at primary sites as a possible prognostic factor of cutaneous angiosarcoma. International Journal of Cancer. [Online] 2014;134(10): 2393–2402. Available from: doi:10.1002/ijc.28581 [Accessed: 12th September 2017]

89.  Qin Z, Blankenstein T. A cancer immunosurveillance controversy. Nat Immunol. [Online] 2004;5(1): 3–5. Available from: doi:10.1038/ni0104-3

90.  Goossens N, Hoshida Y. Hepatitis C virus-induced hepatocellular carcinoma. Clinical and molecular hepatology. [Online] Korean Association for the Study of the Liver; 2015;21(2): 105– 114. Available from: doi:10.3350/cmh.2015.21.2.105 [Accessed: 18th April 2018]

 

91.  Xu C, Zhou W, Wang Y, Qiao L. Hepatitis B virus-induced hepatocellular carcinoma. [Online] Cancer Letters. 2014. p. 216–222. Available from: doi:10.1016/j.canlet.2013.08.035 [Accessed: 5th September 2017]

92.  Wang F, Meng W, Wang B, Qiao L. Helicobacter pylori-induced gastric inflammation and gastric cancer. [Online] Cancer Letters. 2014. p. 196–202. Available from: doi:10.1016/j.canlet.2013.08.016 [Accessed: 5th September 2017]

93.  Rhodes JM, Campbell BJ. Inflammation and colorectal cancer: IBD-associated and sporadic cancer compared. [Online] Trends in Molecular Medicine. Elsevier; 2002. p. 10–16. Available from: doi:10.1016/S1471-4914(01)02194-3 [Accessed: 5th September 2017]

94.  Azer SA. Overview of molecular pathways in inflammatory bowel disease associated with colorectal cancer development. European journal of gastroenterology & hepatology. [Online] European Journal of Gastroenterology & Hepatology; 2013;25(3): 271–281. Available from: doi:10.1097/MEG.0b013e32835b5803 [Accessed: 5th September 2017]

95.  Lin W-W, Karin M. A cytokine - mediated link between innate immunity , inflammation , and cancer. Journal of Clinical Investigation. [Online] 2007;117(5): 1175–1183. Available from: doi:10.1172/JCI31537 [Accessed: 5th September 2017]

96.  Karin M. Nuclear factor-κB in cancer development and progression. Nature. [Online] 2006;441(7092): 431–436. Available from: doi:10.1038/nature04870

97.  Bhatelia K, Singh K, Singh R. TLRs: Linking inflammation and breast cancer. [Online] Cellular Signalling. 2014. p. 2350–2357. Available from: doi:10.1016/j.cellsig.2014.07.035 [Accessed: 5th September 2017]

98.  Calì B, Molon B, Viola A. Tuning cancer fate: the unremitting role of host immunity. Open Biology. [Online] 2017;7(4): 170006. Available from: doi:10.1098/rsob.170006 [Accessed: 4th September 2017]

99.  Garg AD, Galluzzi L, Apetoh L, Baert T, Birge RB, Bravo-San Pedro JM, et al. Molecular and translational classifications of DAMPs in immunogenic cell death. Frontiers in Immunology. [Online] 2015;6(NOV). Available from: doi:10.3389/fimmu.2015.00588 [Accessed: 24th August 2017]

100.  Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. [Online] 2013;501(7467): 338–345. Available from: doi:10.1038/nature12625 [Accessed: 18th September 2017]

101.  Johnsen AK, Templeton DJ, Sy M, Harding C V. Deficiency of transporter for antigen presentation (TAP) in tumor cells allows evasion of immune surveillance and increases tumorigenesis. Journal of immunology (Baltimore, Md. : 1950). [Online] 1999;163(8): 4224–4231. Available from: https://www.scopus.com/record/display.uri?eid=2-s2.00032876395&origin=i… [Accessed: 18thSeptember 2017]

102.  Rotem-Yehudar R, Groettrup M, Soza A, Kloetzel PM, Ehrlich R. LMP-associated proteolytic activities and TAP-dependent peptide transport for class 1 MHC molecules are suppressed in cell lines transformed by the highly oncogenic adenovirus 12. The Journal of experimental medicine. [Online] 1996;183(2): 499–514. Available from: doi:10.1084/jem.183.2.499 [Accessed: 18th September 2017]

103.  Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases-elimination, equilibrium and escape. [Online] Current Opinion in Immunology. 2014. p. 16–25. Available from: doi:10.1016/j.coi.2014.01.004 [Accessed: 4th September 2017]

104.  Khong HT, Restifo NP. Natural selection of tumor variants in the generation of ‘tumor escape’ phenotypes. Nature immunology. [Online] 2002;3(11): 999–1005. Available from: doi:10.1038/ni1102-999 [Accessed: 19th September 2017]

105.  Fulda S. Tumor resistance to apoptosis. International Journal of Cancer. [Online] 2009;124(3): 511–515. Available from: doi:10.1002/ijc.24064

106.  Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, et al. Inhibition of death receptor signals by cellular FLIP. Nature. [Online] 1997;388(6638): 190–195. Available from: doi:10.1038/40657

107.  Oft M. IL-10: Master Switch from Tumor-Promoting Inflammation to Antitumor Immunity. Cancer Immunology Research. [Online] 2014;2(3): 194–199. Available from: doi:10.1158/23266066.CIR-13-0214 [Accessed: 19th September 2017]

108.  Mannino MH, Zhu Z, Xiao H, Bai Q, Wakefield MR, Fang Y. The paradoxical role of IL-10 in immunity and cancer. [Online] Cancer Letters. 2015. p. 103–107. Available from: doi:10.1016/j.canlet.2015.07.009 [Accessed: 19th September 2017]

109.  Pickup M, Novitskiy S, Moses HL. The roles of TGFβ in the tumour microenvironment. Nature Reviews Cancer. [Online] 2013;13(11): 788–799. Available from: doi:10.1038/nrc3603 [Accessed: 3rd October 2017]

110.  Schupp J, Krebs FK, Schuppan D, Tuettenberg A. Targeting myeloid cells in the tumor sustaining microenvironment. Cellular Immunology. [Online] Elsevier; 2017;(October): 0–1. Available from: doi:10.1016/j.cellimm.2017.10.013

111.  Hansen JM, Coleman RL, Sood AK. Targeting the tumour microenvironment in ovarian cancer. [Online] European Journal of Cancer. 2016. p. 131–143. Available from: doi:10.1016/j.ejca.2015.12.016 [Accessed: 8th September 2017]

112.  Hagemann T, Wilson J, Burke F, Kulbe H, Li NF, Plüddemann A, et al. Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. Journal of immunology (Baltimore,Md. : 1950). [Online] American Association of Immunologists; 2006;176(8): 5023–5032. Available from: doi:10.4049/JIMMUNOL.176.8.5023 [Accessed: 14th April 2018]

113.  Reinartz S, Schumann T, Finkernagel F, Wortmann A, Jansen JM, Meissner W, et al. Mixedpolarization phenotype of ascites-associated macrophages in human ovarian carcinoma: Correlation of CD163 expression, cytokine levels and early relapse. Available from: doi:10.1002/ijc.28335 [Accessed: 14th April 2018]

114.  Cui TX, Kryczek I, Zhao L, Zhao E, Kuick R, Roh MH, et al. Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CTBP2. Immunity. [Online] 2013;39(3): 611–621. Available from: doi:10.1016/j.immuni.2013.08.025 [Accessed: 4th October 2017]

115.  Rattan R, Dar S, Rasool N, Ali-Fehmi R, Giri S, Munkarah AR. Depletion of immunosuppressive myeloid-derived suppressor cells impedes ovarian cancer growth. Gynecologic Oncology. [Online] Elsevier Inc.; 2017;145(January 2015): 213–214. Available from: doi:10.1016/j.ygyno.2017.03.491

116.  Zhang B, Chen F, Xu Q, Han L, Xu J, Gao L, et al. Revisiting ovarian cancer microenvironment: a friend or a foe? Protein & Cell. [Online] Higher Education Press; 2017; Available from: doi:10.1007/s13238-017-0466-7

117.  Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. [Online] Cell. 2011. p. 646–674. Available from: doi:10.1016/j.cell.2011.02.013 [Accessed: 23rd August 2017]

118.  Aghajanian C, Blank S V., Goff BA, Judson PL, Teneriello MG, Husain A, et al. OCEANS: A randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. Journal of Clinical Oncology. [Online] 2012;30(17): 2039–2045. Available from: doi:10.1200/JCO.2012.42.0505

119.  Aghajanian C, Goff B, Nycum L, Wang Y, Husain A, Blank S. Final analysis of overall survival in OCEANS, a randomized phase III trial of gemcitabine, carboplatin, and bevacizumab followed by bevacizumab until disease progression in patients with platinum-sensitive recurrent ovarian cancer. Gynecologic Oncology. [Online] Elsevier B.V.; 2014;133: 57. Available from: doi:10.1016/j.ygyno.2014.03.157

120.  Coleman RL, Brady MF, Herzog TJ, Sabbatini P, Armstrong DK, Walker JL, et al. Bevacizumab and paclitaxel–carboplatin chemotherapy and secondary cytoreduction in recurrent, platinumsensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. The Lancet Oncology. [Online] Elsevier Ltd; 2017;18(6): 779–791. Available from: doi:10.1016/S1470-2045(17)30279-6

121.  Hinshaw DB, Hoxie HJ. Leukemoid reactions in carcinomas. Calif Med. 1949;71(4).  

122.  Krystal G, Sly L, Antignano F, Ho V, Ruschmann J, Hamilton M. Re: The terminology issue for myeloid-derived suppressor cells. [Online] Cancer Research. 2007. p. 3986. Available from: doi:10.1158/0008-5472.CAN-07-0211 [Accessed: 21st August 2017]

123.  Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer immunology, immunotherapy : CII. [Online] NIH Public Access; 2009;58(1): 49–59. Available from: doi:10.1007/s00262-008-0523-4 [Accessed: 25th October 2017]

124.  Napoletano C, Bellati F, Landi R, Pauselli S, Marchetti C, Visconti V, et al. Ovarian cancer cytoreduction induces changes in T cell population subsets reducing immunosuppression. Journal of Cellular and Molecular Medicine. [Online] 2010;14(12): 2748–2759. Available from: doi:10.1111/j.1582-4934.2009.00911.x [Accessed: 25th October 2017]

125.  Rashid OM, Nagahashi M, Ramachandran S, Graham L, Yamada A, Spiegel S, et al. Resection of the Primary Tumor Improves Survival in Metastatic Breast Cancer by Reduction of Overall Tumor Burden Conclusions—Decreasing overall tumor burden through resection of the primary breast tumor decreased MDSCs, increased CD4 and CD8 cells, and i. Surgery. [Online] 2013;153(6): 771–778. Available from: doi:10.1016/j.surg.2013.02.002 [Accessed: 25th October 2017]

126.  Predina JD, Kapoor V, Judy BF, Cheng G, Fridlender ZG, Albelda SM, et al. Cytoreduction surgery reduces systemic myeloid suppressor cell populations and restores intratumoral immunotherapy effectiveness. Journal of hematology & oncology. [Online] 2012;5: 34. Available from: doi:10.1186/1756-8722-5-34 [Accessed: 25th October 2017]

127.  Zhao Y, Wu T, Shao S, Shi B, Zhao Y. Phenotype, development, and biological function of myeloid-derived suppressor cells. Oncoimmunology. [Online] 2016;5(2): e1004983. Available from: doi:10.1080/2162402X.2015.1004983

128.  Bronte V, Wang M, Overwijk WW, Surman DR, Pericle F, Rosenberg SA, et al. Apoptotic death of CD8+ T lymphocytes after immunization: induction of a suppressive population of Mac-1+/Gr1+ cells. Journal of immunology (Baltimore, Md. : 1950). [Online] 1998;161(10): 5313–5320. Available from: doi:10.1097/OPX.0b013e3182540562.The [Accessed: 27th September 2017]

129.  Dolcetti L, Peranzoni E, Ugel S, Marigo I, Gomez AF, Mesa C, et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. European Journal of Immunology. [Online] 2010;40(1): 22–35. Available from: doi:10.1002/eji.200939903

130.  Elliott LA, Doherty GA, Sheahan K, Ryan EJ. Human tumor-infiltrating myeloid cells: Phenotypic and functional diversity. [Online] Frontiers in Immunology. 2017. Available from: doi:10.3389/fimmu.2017.00086 [Accessed: 24th October 2017]

131.  Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nature Reviews Immunology. [Online] 2012;12(4): 253–268. Available from: doi:10.1038/nri3175 [Accessed: 26th September 2017]

132.  Mace TA, Ameen Z, Collins A, Wojcik S, Mair M, Young GS, et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a StAT3-dependent manner. Cancer Research. [Online] 2013;73(10): 3007–3018. Available from: doi:10.1158/00085472.CAN-12-4601 [Accessed: 30th October 2017]

133.  Pan PY, Wang GX, Yin B, Ozao J, Ku T, Divino CM, et al. Reversion of immune tolerance in advanced malignancy: Modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function. Blood. [Online] American Society of Hematology; 2008;111(1): 219– 228. Available from: doi:10.1182/blood-2007-04-086835 [Accessed: 30th October 2017]

134.  Umansky V, Blattner C, Gebhardt C, Utikal J. The Role of Myeloid-Derived Suppressor Cells (MDSC) in Cancer Progression. Vaccines. [Online] 2016;4(4): 36. Available from: doi:10.3390/vaccines4040036

135.  Lesokhin AM, Hohl TM, Kitano S, Cortez C, Hirschhorn-Cymerman D, Avogadri F, et al. Monocytic CCR2 + myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment. Cancer Research. [Online] 2012;72(4): 876–886. Available from: doi:10.1158/0008-5472.CAN-11-1792 [Accessed: 4th September 2017]

136.  Lechner MG, Liebertz DJ, Epstein AL. Characterization of Cytokine-Induced Myeloid-Derived Suppressor Cells from Normal Human Peripheral Blood Mononuclear Cells. The Journal of Immunology. [Online] 2010;185(4): 2273–2284. Available from: doi:10.4049/jimmunol.1000901 [Accessed: 26th September 2017]

137.  Jung K, Heishi T, Khan OF, Kowalski PS, Incio J, Rahbari NN, et al. Ly6C lo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy. The Journal of clinical investigation. [Online] 2017;127(8): 1–13. Available from: doi:10.1172/JCI93182

138.  Moshe Elkabets, Vera S.G. Ribeiro, Charles A. Dinarello SO-, Rosenberg, James P. Di Santo, Ron N. Apte  and CAJV. IL-1β regulates a novel myeloid-derived suppressor cell subset that impairs NK cell development and function. European Journal of Immunology. [Online] 2010;40(12): 3347–3357. Available from: doi:10.1016/j.micinf.2011.07.011.Innate [Accessed: 29th October 2017]

139.  Tu S, Bhagat G, Cui G, Takaishi S, Kurt-Jones EA, Rickman B, et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell. [Online] 2008;14(5): 408–419. Available from: doi:10.1016/j.ccr.2008.10.011 [Accessed: 29th October 2017]

140.  Parker KH, Beury DW, Ostrand-Rosenberg S. Myeloid-Derived Suppressor Cells: Critical Cells Driving Immune Suppression in the Tumor Microenvironment. Advances in Cancer Research [Online] 2015;128: 95–139. Available from: doi:10.1016/bs.acr.2015.04.002 [Accessed: 3rd October 2017]

141.  Huang B, Lei Z, Zhao J, Gong W, Liu J, Chen Z, et al. CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers. Cancer Letters. [Online] Elsevier; 2007;252(1): 86–92. Available from: doi:10.1016/j.canlet.2006.12.012 [Accessed: 26th October 2017]

142.  Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature. [Online] NIH Public Access; 2011;475(7355): 222–225. Available from: doi:10.1038/nature10138 [Accessed: 26th October 2017]

143.  Obermajer N, Muthuswamy R, Odunsi K, Edwards RP, Kalinski P. PGE 2-induced CXCL 12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Research. [Online] NIH Public Access; 2011;71(24): 7463–7470. Available from: doi:10.1158/0008-5472.CAN-11-2449 [Accessed: 26th October 2017]

144.  Gabrilovich DI. Myeloid-Derived Suppressor Cells. Cancer Immunology Research. [Online] 2017;5(1): 3–8. Available from: doi:10.1158/2326-6066.CIR-16-0297 [Accessed: 26th September 2017]

145.  Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, et al. Arginase I Production in the Tumor Microenvironment by Mature Myeloid Cells Inhibits T-Cell Receptor Expression and Antigen-Specific T-Cell Responses Arginase I Production in the Tumor Microenvironment by Mature Myeloid Cells Inhibits T-Cell Receptor Expr. Cancer Research. [Online] 2004;64(504): 5839–5849. Available from: doi:10.1158/0008-5472.CAN-04-0465 [Accessed: 28th September 2017]

146.  Rodriguez PC, Zea AH, Culotta KS, Zabaleta J, Ochoa JB, Ochoa AC. Regulation of T Cell Receptor CD3ζ Chain Expression byl-Arginine. Journal of Biological Chemistry. [Online] 2002;277(24): 21123–21129. Available from: doi:10.1074/jbc.M110675200 [Accessed: 29th September 2017]

147.  Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Research. [Online] 2010;70(1): 68–77. Available from: doi:10.1158/0008-5472.CAN-09-2587 [Accessed: 29th September 2017]

148.  Corzo CA, Cotter MJ, Cheng P, Cheng F, Kusmartsev S, Sotomayor E, et al. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. Journal of immunology (Baltimore, Md. : 1950). [Online] 2009;182(9): 5693–5701. Available from: doi:10.4049/jimmunol.0900092 [Accessed: 2nd October 2017]

149.  Mazzoni A, Bronte V, Visintin A, Spitzer JH, Apolloni E, Serafini P, et al. Myeloid Suppressor Lines Inhibit T Cell Responses by an NO-Dependent Mechanism. The Journal of Immunology [Online] 2002;168(2): 689–695. Available from: doi:10.4049/jimmunol.168.2.689 [Accessed: 29th September 2017]

150.  Lu G, Zhang R, Geng S, Peng L, Jayaraman P, Chen C, et al. Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. Nature Communications. [Online] 2015;6: 6676. Available from: doi:10.1038/ncomms7676 [Accessed: 29th September 2017]

151.  Hanson EM, Clements VK, Sinha P, Ilkovitch D, Ostrand-Rosenberg S. Myeloid-Derived Suppressor Cells Down-Regulate L-Selectin Expression on CD4+ and CD8+ T Cells. The Journal of Immunology. [Online] 2009;183(2): 937–944. Available from: doi:10.4049/jimmunol.0804253 [Accessed: 29th September 2017]

152.  Greenwald RJ, Freeman GJ, Sharpe AH. THE B7 FAMILY REVISITED. Annual Review of Immunology. [Online] 2005;23(1): 515–548. Available from: doi:10.1146/annurev.immunol.23.021704.115611 [Accessed: 3rd October 2017]

153.  Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Klöppel G, et al. Stat3/Socs3 Activation by IL-6 Transsignaling Promotes Progression of Pancreatic Intraepithelial Neoplasia and Development of Pancreatic Cancer. Cancer Cell. [Online] 2011;19(4): 456–469. Available from: doi:10.1016/j.ccr.2011.03.009 [Accessed: 29th October 2017]

154.  Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, et al. IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated Cancer. Cancer Cell. [Online] 2009;15(2): 103–113. Available from: doi:10.1016/j.ccr.2009.01.001 [Accessed: 29th October 2017]

155.  Hanahan D, Weinberg RA, Pan KH, Shay JW, Cohen SN, Taylor MB, et al. Hallmarks of Cancer: The Next Generation. Cell. [Online] 2011;144(5): 646–674. Available from: doi:10.1016/j.cell.2011.02.013 [Accessed: 1st September 2017]

156.  Ichikawa M, Williams R, Wang L, Vogl T, Srikrishna G. S100A8/A9 activate key genes and pathways in colon tumor progression. Mol cancer res. [Online] 2011;9(2): 133–148. Available from: doi:10.1158/1541-7786.MCR-10-0394.S100A8/A9

157.  Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell. [Online] 2004;6(4): 409–421. Available from: doi:10.1016/j.ccr.2004.08.031 [Accessed: 30th October 2017]

158.  Boros P, Ochando J, Zeher M. Myeloid derived suppressor cells and autoimmunity. Immunology of the Skin: Basic and Clinical Sciences in Skin Immune Responses. [Online] 2016;77: 179–192. Available from: doi:10.1007/978-4-431-55855-2_11 [Accessed: 14th December 2017]

59.  Ost M, Singh A, Peschel A, Mehling R, Rieber N, Hartl D. Myeloid-Derived Suppressor Cells in Bacterial Infections. Frontiers in Cellular and Infection Microbiology. [Online] 2016;6. Available from: doi:10.3389/fcimb.2016.00037 [Accessed: 14th December 2017]

160.  Fujita K, Ikarashi H, Takakuwa K, Kodama S, Tokunaga A, Takahashi T, et al. Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes. Clinical cancer research. [Online] 1995;1(5): 501–507. Available from: http://clincancerres.aacrjournals.org/content/clincanres/1/5/501.full.p… [Accessed: 18th October 2017]

161.  Varga A, Oha-Paul SA, Ott PA, Mehnert JM, Berton-Rigaud D, Johnson EA, et al. Antitumor activity and safety of pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian cancer: Interim results from a phase Ib study. Journal of Clinical Oncology. [Online] 2015;55: 5510–5510. Available from: doi:10.1200/JCO.2015.33.15_SUPPL.5510

162.  Hamanishi J, Mandai M, Ikeda T, Minami M, Kawaguchi A, Murayama T, et al. Safety and antitumor activity of Anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. Journal of Clinical Oncology. [Online] 2015;33(34): 4015–4022. Available from: doi:10.1200/JCO.2015.62.3397 [Accessed: 18th October 2017]

163.  Disis ML, Patel MR, Pant S, Infante JR, Lockhart AC, Kelly K, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory ovarian cancer: A phase Ib, open-label expansion trial. Journal of Clinical Oncology. [Online] 2015;33(15): 5509. Available from: doi:DOI: 10.1200/jco.2015.33.15_suppl.5509

164.  Inaba T, Ino K, Kajiyama H, Yamamoto E, Shibata K, Nawa A, et al. Role of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in the progression of ovarian carcinoma. Gynecologic Oncology. [Online] Elsevier; 2009;115(2): 185–192. Available from: doi:10.1016/j.ygyno.2009.07.015 [Accessed: 18th October 2017]

165.  Baert T. Dendritic cell immunotherapy in ovarian cancer: a murine model. 2018.  

166.  Hodi FS, Butler M, Oble DA, Seiden M V., Haluska FG, Kruse A, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proceedings of the National Academy of Sciences. [Online] 2008;105(8): 3005–3010. Available from: doi:10.1073/pnas.0712237105 [Accessed: 19th April 2018]

167.  Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, et al. Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer. New England Journal of Medicine. [Online] 2012;366(26): 2455–2465. Available from: doi:10.1056/NEJMoa1200694 [Accessed: 19th April 2018]

168.  Hamanishi J, Mandai M, Ikeda T. Durable tumor remission in patients with platinum-resistant ovarian cancer receiving nivolumab. Journal of Clinical Oncology. 2015;33(15): 5570.  

169.  Lee J-M, Cimino-Mathews A, Peer CJ, Zimmer A, Lipkowitz S, Annunziata CM, et al. Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women’s Cancers: A Dose-Escalation, Phase I Study. Journal of Clinical Oncology. [Online] 2017;35(19): 2193–2202. Available from: doi:10.1200/JCO.2016.72.1340 [Accessed: 19th April 2018]

170.  Infante JR, Braiteh F, Emens LA, Balmanoukian AS, Oaknin A, Wang Y, et al. Safety, clinical activity and biomarkers of atezolizumab (atezo) in advanced ovarian cancer (OC). Annals of Oncology. [Online] Oxford University Press; 2016;27(suppl_6). Available from: doi:10.1093/annonc/mdw374.18 [Accessed: 19th April 2018]

171.  Motz GT, Santoro SP, Wang L-P, Garrabrant T, Lastra RR, Hagemann IS, et al. Tumor Endothelium FasL Establishes a Selective Immune Barrier Promoting Tolerance in Tumors. Nature Medicine. [Online] 2014;20(6): 607–615. Available from: doi:10.1038/nm.3541 [Accessed: 22nd January 2018]

172.  Welters MJ, van der Sluis TC, van Meir H, Loof NM, van Ham VJ, van Duikeren S, et al. Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses. Science translational medicine. [Online] American Association for the Advancement of Science; 2016;8(334): 334ra52. Available from: doi:10.1126/scitranslmed.aad8307 [Accessed: 20th May 2018]

173.  Vankerckhoven A, Baert T, Ruts H, Vergote I, Coosemans A. Combining conventional therapy with immunotherapy: a risky business? CIMT congress. Mainz, Germany; 2018.  

174.  Baert T, Verschuere T, Van Hoylandt A, Gijsbers R, Vergote I, Coosemans A. The dark side of ID8-Luc2: pitfalls for luciferase tagged murine models for ovarian cancer. Journal for immunotherapy of cancer. [Online] 2015;3(1): 57. Available from: doi:10.1186/s40425-015-01020 [Accessed: 21st August 2017]

175.  Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: Open source software for digital pathology image analysis. Scientific reports. [Online] Nature Publishing Group; 2017;7(1): 16878. Available from: doi:10.1038/s41598-017-17204-5 [Accessed: 9th May 2018]

176.  Hong EH, Chang SY, Lee BR, Kim YS, Lee JM, Kang CY, et al. Blockade of Myd88 signaling induces antitumor effects by skewing the immunosuppressive function of myeloid-derived suppressor cells. International Journal of Cancer. [Online] Wiley Subscription Services, Inc., A Wiley Company; 2013;132(12): 2839–2848. Available from: doi:10.1002/ijc.27974 [Accessed: 24th January 2018]

177.  Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. [Online] Cancer Cell. 2015. p. 690–714. Available from: doi:10.1016/j.ccell.2015.10.012 [Accessed: 30th August 2017]

178.  Hamanishi J, Mandai M, Konishi I. Immune checkpoint inhibition in ovarian cancer. International Immunology. [Online] 2016;28(7): 339–348. Available from: doi:10.1093/intimm/dxw020[Accessed: 30th August 2017]

179.  Jindal V, Arora E, Gupta S, Lal A, Masab M, Potdar R. Prospects of chimeric antigen receptor T cell therapy in ovarian cancer. Medical Oncology. [Online] Springer US; 2018;35(5): 70. Available from: doi:10.1007/s12032-018-1131-6

180.  Ribas A. Adaptive immune resistance: How cancer protects from immune attack. Cancer Discovery. [Online] 2015;5(9): 915–919. Available from: doi:10.1158/2159-8290.CD-15-0563

181.  Ben-Meir K, Twaik N, Baniyash M. Plasticity and biological diversity of myeloid derived suppressor cells. Current Opinion in Immunology. [Online] Elsevier Ltd; 2018;51: 154–161. Available from: doi:10.1016/j.coi.2018.03.015

182.  Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nature Communications. [Online] 2016;7. Available from: doi:10.1038/ncomms12150 [Accessed: 27th September 2017]

183.  Ugel S, Peranzoni E, Desantis G, Chioda M, Walter S, Weinschenk T, et al. Immune tolerance to tumor antigens occurs in a specialized environment of the spleen. Cell reports. [Online] Elsevier; 2012;2(3): 628–639. Available from: doi:10.1016/j.celrep.2012.08.006 [Accessed: 21st May 2018]

184.  Alberts DS, Marth C, Alvarez RD, Johnson G, Bidzinski M, Kardatzke DR, et al. Randomized phase 3 trial of interferon gamma-1b plus standard carboplatin/paclitaxel versus carboplatin/paclitaxel alone for first-line treatment of advanced ovarian and primary peritoneal carcinomas: Results from a prospectively designed analysis of progression-free survival. Gynecologic Oncology. [Online] 2008;109(2): 174–181. Available from: doi:10.1016/j.ygyno.2008.01.005 [Accessed: 26th April 2018]

185.  Medina-Echeverz J, Haile LA, Zhao F, Gamrekelashvili J, Ma C, Métais JY, et al. IFN-γ regulates survival and function of tumor-induced CD11b+Gr-1high myeloid derived suppressor cells by modulating the anti-apoptotic molecule Bcl2a1. European Journal of Immunology. [Online] 2014;44(8): 2457–2467. Available from: doi:10.1002/eji.201444497

Universiteit of Hogeschool
Biomedische wetenschappen: Biomedisch basis- en translationeel onderzoek
Publicatiejaar
2018
Promotor(en)
An Coosemans
Kernwoorden
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