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CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2021; 81(10): 1128-1144
DOI: 10.1055/a-1475-4335
DOI: 10.1055/a-1475-4335
GebFra Science
Review/Übersicht
Immunology and Immune Checkpoint Inhibition in Ovarian Cancer – Current Aspects
Artikel in mehreren Sprachen: English | deutsch
Abstract
In the last decade immunotherapies such as immune checkpoint blockade (ICB) against the PD-1/PD-L1 system have revolutionised the treatment of numerous entities. To date, ovarian cancer has benefited very little from this success story. Possible causes include a rather low mutational burden compared to other tumour types, inadequate presentation of (neo-)antigens, and increased infiltration with immunosuppressive immune cells such as regulatory T cells and tumour-associated macrophages. In the clinical trials completed to date, the response rates to PD-1/PD-L1 checkpoint inhibitors have therefore been disappointingly low as well, although isolated long-term remissions have also been observed in ovarian cancer. The task now is to find suitable predictive biomarkers as well as to identify combination partners for ICB therapy that can increase the immunogenicity of ovarian cancer or overcome immunosuppressive resistance mechanisms. This paper provides an overview of the immune milieu in ovarian cancer, its impact on the effect of ICB, and summarises the clinical trial data available to date on ICB in ovarian cancer.
Publikationsverlauf
Eingereicht: 24. Januar 2021
Angenommen nach Revision: 05. April 2021
Artikel online veröffentlicht:
06. Juli 2021
© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
Georg Thieme Verlag KG
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References/Literatur
- 1 Tyzzer EE. Tumor Immunity. Am J Cancer Res 1916; 1: 125-156
- 2 Maman S, Witz IP. A history of exploring cancer in context. Nat Rev Cancer 2018; 18: 359-376 DOI: 10.1038/s41568-018-0006-7.
- 3 Galluzzi L, Buque A, Kepp O. et al. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell 2015; 28: 690-714 DOI: 10.1016/j.ccell.2015.10.012.
- 4 Marth C, Wieser V, Tsibulak I. et al. Immunotherapy in ovarian cancer: fake news or the real deal?. Int J Gynecol Cancer 2019; 29: 201-211 DOI: 10.1136/ijgc-2018-000011.
- 5 Moore KN, Bookman M, Sehouli J. et al. Primary results from IMagyn050/GOG 3015/ENGOT-OV39, a double-blind placebo (pbo)-controlled randomised phase III trial of bevacizumab (bev)-containing therapy +/- atezolizumab (atezo) for newly diagnosed stage III/IV ovarian cancer (OC). Ann Oncol 2020; 31: S1161-S1162 DOI: 10.1016/j.annonc.2020.08.2261.
- 6 Moore K. Primary results from IMagyn050/GOG 3015/ENGOT-OV39, a double-blind placebo-controlled randomised phase 3 trial of bevacizumab-containing therapy ± atezolizumab for newly diagnosed stage III/IV ovarian cancer. ESMO 2020. J Clin Oncol 2021; 39: 1842-1855 DOI: 10.1200/JCO.21.00306.
- 7 Lampert EJ, Zimmer A, Padget M. et al. Combination of PARP Inhibitor Olaparib, and PD-L1 Inhibitor Durvalumab, in Recurrent Ovarian Cancer: a Proof-of-Concept Phase II Study. Clin Cancer Res 2020; 26: 4268-4279 DOI: 10.1158/1078-0432.CCR-20-0056.
- 8 Konstantinopoulos PA, Waggoner S, Vidal GA. et al. Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma. JAMA Oncol 2019; DOI: 10.1001/jamaoncol.2019.1048.
- 9 Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 2004; 22: 329-360 DOI: 10.1146/annurev.immunol.22.012703.104803.
- 10 Alexandrov LB, Nik-Zainal S, Wedge DC. et al. Signatures of mutational processes in human cancer. Nature 2013; 500: 415-421 DOI: 10.1038/nature12477.
- 11 Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science 2015; 348: 69-74 DOI: 10.1126/science.aaa4971.
- 12 Chalmers ZR, Connelly CF, Fabrizio D. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 2017; 9: 34 DOI: 10.1186/s13073-017-0424-2.
- 13 Wick DA, Webb JR, Nielsen JS. et al. Surveillance of the tumor mutanome by T cells during progression from primary to recurrent ovarian cancer. Clin Cancer Res 2014; 20: 1125-1134 DOI: 10.1158/1078-0432.CCR-13-2147.
- 14 Yarchoan M, Johnson 3rd BA, Lutz ER. et al. Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer 2017; 17: 569 DOI: 10.1038/nrc.2017.74.
- 15 Cristescu R, Mogg R, Ayers M. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 2018; DOI: 10.1126/science.aar3593.
- 16 Zhang AW, McPherson A, Milne K. et al. Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer. Cell 2018; 173: 1755-1769.e22 DOI: 10.1016/j.cell.2018.03.073.
- 17 The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474: 609-615 DOI: 10.1038/nature10166.
- 18 Wang RF, Wang HY. Immune targets and neoantigens for cancer immunotherapy and precision medicine. Cell Res 2017; 27: 11-37 DOI: 10.1038/cr.2016.155.
- 19 Schuster H, Peper JK, Bosmuller HC. et al. The immunopeptidomic landscape of ovarian carcinomas. Proc Natl Acad Sci U S A 2017; 114: E9942-E9951 DOI: 10.1073/pnas.1707658114.
- 20 Want MY, Lugade AA, Battaglia S. et al. Nature of tumour rejection antigens in ovarian cancer. Immunology 2018; 155: 202-210 DOI: 10.1111/imm.12951.
- 21 Rodriguez GM, Galpin KJC, McCloskey CW. et al. The Tumor Microenvironment of Epithelial Ovarian Cancer and Its Influence on Response to Immunotherapy. Cancers (Basel) 2018; 10: 242 DOI: 10.3390/cancers10080242.
- 22 Ma D, Gu MJ. Immune effect of tumor-infiltrating lymphocytes and its relation to the survival rate of patients with ovarian malignancies. J Tongji Med Univ 1991; 11: 235-239 DOI: 10.1007/BF02888158.
- 23 Zhang L, Conejo-Garcia JR, Katsaros D. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003; 348: 203-213
- 24 Konecny GE, Wang C, Hamidi H. et al. Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer. J Natl Cancer Inst 2014; DOI: 10.1093/jnci/dju249.
- 25 Tothill RW, Tinker AV, George J. et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res 2008; 14: 5198-5208 DOI: 10.1158/1078-0432.CCR-08-0196.
- 26 Wang C, Armasu SM, Kalli KR. et al. Pooled Clustering of High-Grade Serous Ovarian Cancer Gene Expression Leads to Novel Consensus Subtypes Associated with Survival and Surgical Outcomes. Clin Cancer Res 2017; 23: 4077-4085 DOI: 10.1158/1078-0432.CCR-17-0246.
- 27 Clarke B, Tinker AV, Lee CH. et al. Intraepithelial T cells and prognosis in ovarian carcinoma: novel associations with stage, tumor type, and BRCA1 loss. Mod Pathol 2009; 22: 393-402 DOI: 10.1038/modpathol.2008.191.
- 28 Hamanishi J, Mandai M, Iwasaki M. et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A 2007; 104: 3360-3365 DOI: 10.1073/pnas.0611533104.
- 29 Knutson KL, Maurer MJ, Preston CC. et al. Regulatory T cells, inherited variation, and clinical outcome in epithelial ovarian cancer. Cancer Immunol Immunother 2015; 64: 1495-1504 DOI: 10.1007/s00262-015-1753-x.
- 30 Montfort A, Owen S, Piskorz AM. et al. Combining measures of immune infiltration shows additive effect on survival prediction in high-grade serous ovarian carcinoma. Br J Cancer 2020; 122: 1803-1810 DOI: 10.1038/s41416-020-0822-x.
- 31 Sato E, Olson SH, Ahn J. et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 2005; 102: 18538-18543 DOI: 10.1073/pnas.0509182102.
- 32 Hamanishi J, Mandai M, Abiko K. et al. The comprehensive assessment of local immune status of ovarian cancer by the clustering of multiple immune factors. Clin Immunol 2011; 141: 338-347 DOI: 10.1016/j.clim.2011.08.013.
- 33 Tsiatas ML, Gyftaki R, Liacos C. et al. Study of T lymphocytes infiltrating peritoneal metastases in advanced ovarian cancer: associations with vascular endothelial growth factor levels and prognosis in patients receiving platinum-based chemotherapy. Int J Gynecol Cancer 2009; 19: 1329-1334 DOI: 10.1111/IGC.0b013e3181b7a40e.
- 34 deLeeuw RJ, Kroeger DR, Kost SE. et al. CD25 identifies a subset of CD4(+)FoxP3(−) TIL that are exhausted yet prognostically favorable in human ovarian cancer. Cancer Immunol Res 2015; 3: 245-253 DOI: 10.1158/2326-6066.CIR-14-0146.
- 35 Nesbeth YC, Martinez DG, Toraya S. et al. CD4+ T cells elicit host immune responses to MHC class II-negative ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells. J Immunol 2010; 184: 5654-5662 DOI: 10.4049/jimmunol.0903247.
- 36 Abastado JP. The next challenge in cancer immunotherapy: controlling T-cell traffic to the tumor. Cancer Res 2012; 72: 2159-2161 DOI: 10.1158/0008-5472.CAN-11-3538.
- 37 Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013; 39: 1-10 DOI: 10.1016/j.immuni.2013.07.012.
- 38 Bronger H, Singer J, Windmuller C. et al. CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer. Br J Cancer 2016; 115: 553-563 DOI: 10.1038/bjc.2016.172.
- 39 Dangaj D, Bruand M, Grimm AJ. et al. Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors. Cancer Cell 2019; 35: 885-900.e10 DOI: 10.1016/j.ccell.2019.05.004.
- 40 Zsiros E, Duttagupta P, Dangaj D. et al. The Ovarian Cancer Chemokine Landscape Is Conducive to Homing of Vaccine-Primed and CD3/CD28-Costimulated T Cells Prepared for Adoptive Therapy. Clin Cancer Res 2015; 21: 2840-2850 DOI: 10.1158/1078-0432.CCR-14-2777.
- 41 Melero I, Rouzaut A, Motz GT. et al. T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy. Cancer Discov 2014; 4: 522-526 DOI: 10.1158/2159-8290.CD-13-0985.
- 42 Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 2017; DOI: 10.1038/nri.2017.49.
- 43 Jimenez-Sanchez A, Memon D, Pourpe S. et al. Heterogeneous Tumor-Immune Microenvironments among Differentially Growing Metastases in an Ovarian Cancer Patient. Cell 2017; 170: 927-938.e20 DOI: 10.1016/j.cell.2017.07.025.
- 44 Millstein J, Budden T, Goode EL. et al. Prognostic gene expression signature for high-grade serous ovarian cancer. Ann Oncol 2020; DOI: 10.1016/j.annonc.2020.05.019.
- 45 Chow MT, Ozga AJ, Servis RL. et al. Intratumoral Activity of the CXCR3 Chemokine System Is Required for the Efficacy of Anti-PD-1 Therapy. Immunity 2019; 50: 1498-1512.e5 DOI: 10.1016/j.immuni.2019.04.010.
- 46 Shen J, Zhao W, Ju Z. et al. PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness. Cancer Res 2019; 79: 311-319 DOI: 10.1158/0008-5472.CAN-18-1003.
- 47 Liu M, Matsumura N, Mandai M. et al. Classification using hierarchical clustering of tumor-infiltrating immune cells identifies poor prognostic ovarian cancers with high levels of COX expression. Mod Pathol 2009; 22: 373-384 DOI: 10.1038/modpathol.2008.187.
- 48 Plitas G, Rudensky AY. Regulatory T Cells: Differentiation and Function. Cancer Immunol Res 2016; 4: 721-725 DOI: 10.1158/2326-6066.CIR-16-0193.
- 49 Li C, Jiang P, Wei S. et al. Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects. Mol Cancer 2020; 19: 116 DOI: 10.1186/s12943-020-01234-1.
- 50 Sakaguchi S, Sakaguchi N, Asano M. et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155: 1151-1164
- 51 Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4: 330-336 DOI: 10.1038/ni904.
- 52 Gavin MA, Rasmussen JP, Fontenot JD. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 2007; 445: 771-775 DOI: 10.1038/nature05543.
- 53 Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 2007; 8: 277-284 DOI: 10.1038/ni1437.
- 54 Sehouli J, Loddenkemper C, Cornu T. et al. Epigenetic quantification of tumor-infiltrating T-lymphocytes. Epigenetics 2011; 6: 236-246 DOI: 10.4161/epi.6.2.13755.
- 55 Woo EY, Chu CS, Goletz TJ. et al. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 2001; 61: 4766-4772
- 56 Curiel TJ, Coukos G, Zou L. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10: 942-949 DOI: 10.1038/nm1093.
- 57 Barnett JC, Bean SM, Whitaker RS. et al. Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype. Gynecol Oncol 2010; 116: 556-562 DOI: 10.1016/j.ygyno.2009.11.020.
- 58 Wolf D, Wolf AM, Rumpold H. et al. The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin Cancer Res 2005; 11: 8326-8331 DOI: 10.1158/1078-0432.CCR-05-1244.
- 59 Fialova A, Partlova S, Sojka L. et al. Dynamics of T-cell infiltration during the course of ovarian cancer: the gradual shift from a Th17 effector cell response to a predominant infiltration by regulatory T-cells. Int J Cancer 2013; 132: 1070-1079 DOI: 10.1002/ijc.27759.
- 60 Kryczek I, Wei S, Zhu G. et al. Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res 2007; 67: 8900-8905 DOI: 10.1158/0008-5472.CAN-07-1866.
- 61 Curiel TJ, Cheng P, Mottram P. et al. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res 2004; 64: 5535-5538
- 62 Facciabene A, Peng X, Hagemann IS. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 2011; 475: 226-230 DOI: 10.1038/nature10169.
- 63 Wertel I, Surowka J, Polak G. et al. Macrophage-derived chemokine CCL22 and regulatory T cells in ovarian cancer patients. Tumour Biol 2015; 36: 4811-4817 DOI: 10.1007/s13277-015-3133-8.
- 64 Redjimi N, Raffin C, Raimbaud I. et al. CXCR3+ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity. Cancer Res 2012; 72: 4351-4360 DOI: 10.1158/0008-5472.CAN-12-0579.
- 65 Au KK, Peterson N, Truesdell P. et al. CXCL10 alters the tumour immune microenvironment and disease progression in a syngeneic murine model of high-grade serous ovarian cancer. Gynecol Oncol 2017; 145: 436-445 DOI: 10.1016/j.ygyno.2017.03.007.
- 66 Di Pilato M, Kim EY, Cadilha BL. et al. Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy. Nature 2019; 570: 112-116 DOI: 10.1038/s41586-019-1215-2.
- 67 Overacre-Delgoffe AE, Chikina M, Dadey RE. et al. Interferon-gamma Drives Treg Fragility to Promote Anti-tumor Immunity. Cell 2017; 169: 1130-1141.e11 DOI: 10.1016/j.cell.2017.05.005.
- 68 Jung K, Kim JA, Kim YJ. et al. A Neuropilin-1 Antagonist Exerts Antitumor Immunity by Inhibiting the Suppressive Function of Intratumoral Regulatory T Cells. Cancer Immunol Res 2020; 8: 46-56 DOI: 10.1158/2326-6066.CIR-19-0143.
- 69 Kandalaft LE, Chiang CL, Tanyi J. et al. A Phase I vaccine trial using dendritic cells pulsed with autologous oxidized lysate for recurrent ovarian cancer. J Transl Med 2013; 11: 149 DOI: 10.1186/1479-5876-11-149.
- 70 Singh M, Loftus T, Webb E. et al. Minireview: Regulatory T Cells and Ovarian Cancer. Immunol Invest 2016; 45: 712-720 DOI: 10.1080/08820139.2016.1186689.
- 71 de Boo LW, Vulink AJE, Bos M. Metronomic cyclophosphamide-induced long-term remission after recurrent high-grade serous ovarian cancer: A case study. Mol Clin Oncol 2017; 7: 1130-1134 DOI: 10.3892/mco.2017.1457.
- 72 Yang R, Cai Z, Zhang Y. et al. CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1+CD11b+ myeloid cells. Cancer Res 2006; 66: 6807-6815 DOI: 10.1158/0008-5472.CAN-05-3755.
- 73 Colvin EK. Tumor-associated macrophages contribute to tumor progression in ovarian cancer. Front Oncol 2014; 4: 137 DOI: 10.3389/fonc.2014.00137.
- 74 Finkernagel F, Reinartz S, Lieber S. et al. The transcriptional signature of human ovarian carcinoma macrophages is associated with extracellular matrix reorganization. Oncotarget 2016; 7: 75339-75352 DOI: 10.18632/oncotarget.12180.
- 75 Yang M, McKay D, Pollard JW. et al. Diverse Functions of Macrophages in Different Tumor Microenvironments. Cancer Res 2018; 78: 5492-5503 DOI: 10.1158/0008-5472.CAN-18-1367.
- 76 Duluc D, Corvaisier M, Blanchard S. et al. Interferon-gamma reverses the immunosuppressive and protumoral properties and prevents the generation of human tumor-associated macrophages. Int J Cancer 2009; 125: 367-373 DOI: 10.1002/ijc.24401.
- 77 Germano G, Frapolli R, Belgiovine C. et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 2013; 23: 249-262 DOI: 10.1016/j.ccr.2013.01.008.
- 78 Wanderley CW, Colon DF, Luiz JPM. et al. Paclitaxel Reduces Tumor Growth by Reprogramming Tumor-Associated Macrophages to an M1 Profile in a TLR4-Dependent Manner. Cancer Res 2018; 78: 5891-5900 DOI: 10.1158/0008-5472.CAN-17-3480.
- 79 Hagemann T, Wilson J, Burke F. et al. Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J Immunol 2006; 176: 5023-5032 DOI: 10.4049/jimmunol.176.8.5023.
- 80 Reinartz S, Schumann T, Finkernagel F. et al. Mixed-polarization phenotype of ascites-associated macrophages in human ovarian carcinoma: correlation of CD163 expression, cytokine levels and early relapse. Int J Cancer 2014; 134: 32-42 DOI: 10.1002/ijc.28335.
- 81 No JH, Moon JM, Kim K. et al. Prognostic significance of serum soluble CD163 level in patients with epithelial ovarian cancer. Gynecol Obstet Invest 2013; 75: 263-267 DOI: 10.1159/000349892.
- 82 Yuan X, Zhang J, Li D. et al. Prognostic significance of tumor-associated macrophages in ovarian cancer: A meta-analysis. Gynecol Oncol 2017; 147: 181-187 DOI: 10.1016/j.ygyno.2017.07.007.
- 83 Yin M, Li X, Tan S. et al. Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer. J Clin Invest 2016; 126: 4157-4173 DOI: 10.1172/JCI87252.
- 84 Aras S, Zaidi MR. TAMeless traitors: macrophages in cancer progression and metastasis. Br J Cancer 2017; 117: 1583-1591 DOI: 10.1038/bjc.2017.356.
- 85 Zhang J, Yao H, Song G. et al. Regulation of epithelial-mesenchymal transition by tumor-associated macrophages in cancer. Am J Transl Res 2015; 7: 1699-1711
- 86 Kryczek I, Zou L, Rodriguez P. et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 2006; 203: 871-881 DOI: 10.1084/jem.20050930.
- 87 Sica GL, Choi IH, Zhu G. et al. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 2003; 18: 849-861 DOI: 10.1016/s1074-7613(03)00152-3.
- 88 Cassetta L, Kitamura T. Targeting Tumor-Associated Macrophages as a Potential Strategy to Enhance the Response to Immune Checkpoint Inhibitors. Front Cell Dev Biol 2018; 6: 38 DOI: 10.3389/fcell.2018.00038.
- 89 Qu Y, Wen J, Thomas G. et al. Baseline Frequency of Inflammatory Cxcl9-Expressing Tumor-Associated Macrophages Predicts Response to Avelumab Treatment. Cell Rep 2020; 32: 107873 DOI: 10.1016/j.celrep.2020.107873.
- 90 Worzfeld T, Pogge von Strandmann E, Huber M. et al. The Unique Molecular and Cellular Microenvironment of Ovarian Cancer. Front Oncol 2017; 7: 24 DOI: 10.3389/fonc.2017.00024.
- 91 Mantovani A, Marchesi F, Malesci A. et al. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 2017; 14: 399-416 DOI: 10.1038/nrclinonc.2016.217.
- 92 Zhu Y, Knolhoff BL, Meyer MA. et al. CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 2014; 74: 5057-5069 DOI: 10.1158/0008-5472.CAN-13-3723.
- 93 Moughon DL, He H, Schokrpur S. et al. Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer. Cancer Res 2015; 75: 4742-4752 DOI: 10.1158/0008-5472.CAN-14-3373.
- 94 Baci D, Bosi A, Gallazzi M. et al. The Ovarian Cancer Tumor Immune Microenvironment (TIME) as Target for Therapy: A Focus on Innate Immunity Cells as Therapeutic Effectors. Int J Mol Sci 2020; 21: 3125 DOI: 10.3390/ijms21093125.
- 95 Lin H, Wei S, Hurt EM. et al. Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. J Clin Invest 2018; 128: 805-815 DOI: 10.1172/JCI96113.
- 96 Tang H, Liang Y, Anders RA. et al. PD-L1 on host cells is essential for PD-L1 blockade-mediated tumor regression. J Clin Invest 2018; 128: 580-588 DOI: 10.1172/JCI96061.
- 97 Abiko K, Mandai M, Hamanishi J. et al. PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction. Clin Cancer Res 2013; 19: 1363-1374 DOI: 10.1158/1078-0432.CCR-12-2199.
- 98 Krempski J, Karyampudi L, Behrens MD. et al. Tumor-infiltrating programmed death receptor-1+ dendritic cells mediate immune suppression in ovarian cancer. J Immunol 2011; 186: 6905-6913 DOI: 10.4049/jimmunol.1100274.
- 99 Xue C, Xu Y, Ye W. et al. Expression of PD-L1 in ovarian cancer and its synergistic antitumor effect with PARP inhibitor. Gynecol Oncol 2020; 157: 222-233 DOI: 10.1016/j.ygyno.2019.12.012.
- 100 Abiko K, Matsumura N, Hamanishi J. et al. IFN-gamma from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br J Cancer 2015; 112: 1501-1509 DOI: 10.1038/bjc.2015.101.
- 101 Darb-Esfahani S, Kunze CA, Kulbe H. et al. Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma. Oncotarget 2016; 7: 1486-1499 DOI: 10.18632/oncotarget.6429.
- 102 Webb JR, Milne K, Kroeger DR. et al. PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer. Gynecol Oncol 2016; 141: 293-302 DOI: 10.1016/j.ygyno.2016.03.008.
- 103 Hogdall E, Hogdall C, Vo T. et al. Impact of PD-L1 and T-cell inflamed gene expression profile on survival in advanced ovarian cancer. Int J Gynecol Cancer 2020; 30: 1034-1042 DOI: 10.1136/ijgc-2019-001109.
- 104 Chen H, Molberg K, Strickland AL. et al. PD-L1 Expression and CD8+ Tumor-infiltrating Lymphocytes in Different Types of Tubo-ovarian Carcinoma and Their Prognostic Value in High-grade Serous Carcinoma. Am J Surg Pathol 2020; 44: 1050-1060 DOI: 10.1097/PAS.0000000000001503.
- 105 Chin CD, Fares CM, Campos M. et al. Association of PD-L1 expression by immunohistochemistry and gene microarray with molecular subtypes of ovarian tumors. Mod Pathol 2020; 33: 2001-2010 DOI: 10.1038/s41379-020-0567-3.
- 106 Peng J, Hamanishi J, Matsumura N. et al. Chemotherapy Induces Programmed Cell Death-Ligand 1 Overexpression via the Nuclear Factor-kappaB to Foster an Immunosuppressive Tumor Microenvironment in Ovarian Cancer. Cancer Res 2015; 75: 5034-5045 DOI: 10.1158/0008-5472.CAN-14-3098.
- 107 Kodumudi KN, Woan K, Gilvary DL. et al. A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res 2010; 16: 4583-4594 DOI: 10.1158/1078-0432.CCR-10-0733.
- 108 Zhang L, Dermawan K, Jin M. et al. Differential impairment of regulatory T cells rather than effector T cells by paclitaxel-based chemotherapy. Clin Immunol 2008; 129: 219-229 DOI: 10.1016/j.clim.2008.07.013.
- 109 Mouw KW, Konstantinopoulos PA. From checkpoint to checkpoint: DNA damage ATR/Chk1 checkpoint signalling elicits PD-L1 immune checkpoint activation. Br J Cancer 2018; 118: 933-935 DOI: 10.1038/s41416-018-0017-x.
- 110 Khairallah AS, Genestie C, Auguste A. et al. Impact of neoadjuvant chemotherapy on the immune microenvironment in advanced epithelial ovarian cancer: Prognostic and therapeutic implications. Int J Cancer 2018; 143: 8-15 DOI: 10.1002/ijc.31200.
- 111 Lo CS, Sanii S, Kroeger DR. et al. Neoadjuvant Chemotherapy of Ovarian Cancer Results in Three Patterns of Tumor-Infiltrating Lymphocyte Response with Distinct Implications for Immunotherapy. Clin Cancer Res 2017; 23: 925-934 DOI: 10.1158/1078-0432.CCR-16-1433.
- 112 Pölcher M, Braun M, Friedrichs N. et al. Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 2010; 59: 909-919 DOI: 10.1007/s00262-010-0817-1.
- 113 Bohm S, Montfort A, Pearce OM. et al. Neoadjuvant Chemotherapy Modulates the Immune Microenvironment in Metastases of Tubo-Ovarian High-Grade Serous Carcinoma. Clin Cancer Res 2016; 22: 3025-3036 DOI: 10.1158/1078-0432.CCR-15-2657.
- 114 Yaniz E, Genestie C, Klein C. et al. Impact of chemotherapy alone or in combination with an anti-angiogenic on the immune tumor microenvironment (TME) of ovarian cancer: Data from the randomized CHIVA trial (a GINECO –GINEGEPS study). J Clin Oncol 2020; 38 (no. 15_suppl): 6011 DOI: 10.1200/JCO.2020.38.15_suppl.6011.
- 115 Wu X, Feng QM, Wang Y. et al. The immunologic aspects in advanced ovarian cancer patients treated with paclitaxel and carboplatin chemotherapy. Cancer Immunol Immunother 2010; 59: 279-291 DOI: 10.1007/s00262-009-0749-9.
- 116 Mesnage SJL, Auguste A, Genestie C. et al. Neoadjuvant chemotherapy (NACT) increases immune infiltration and programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC). Ann Oncol 2017; 28: 651-657 DOI: 10.1093/annonc/mdw625.
- 117 Napoletano C, Bellati F, Landi R. et al. Ovarian cancer cytoreduction induces changes in T cell population subsets reducing immunosuppression. J Cell Mol Med 2010; 14: 2748-2759 DOI: 10.1111/j.1582-4934.2009.00911.x.
- 118 Bosmuller HC, Wagner P, Peper JK. et al. Combined Immunoscore of CD103 and CD3 Identifies Long-Term Survivors in High-Grade Serous Ovarian Cancer. Int J Gynecol Cancer 2016; DOI: 10.1097/IGC.0000000000000672.
- 119 Strickland KC, Howitt BE, Shukla SA. et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget 2016; 7: 13587-13598 DOI: 10.18632/oncotarget.7277.
- 120 Cardenas H, Jiang G, Thomes Pepin J. et al. Interferon-gamma signaling is associated with BRCA1 loss-of-function mutations in high grade serous ovarian cancer. NPJ Precis Oncol 2019; 3: 32 DOI: 10.1038/s41698-019-0103-4.
- 121 Khoja L, Day D, Wei-Wu Chen T. et al. Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Ann Oncol 2017; 28: 2377-2385 DOI: 10.1093/annonc/mdx286.
- 122 Hwang WT, Adams SF, Tahirovic E. et al. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol 2012; 124: 192-198 DOI: 10.1016/j.ygyno.2011.09.039.
- 123 Hamanishi J, Mandai M, Ikeda T. et al. Safety and Antitumor Activity of Anti-PD-1 Antibody, Nivolumab, in Patients With Platinum-Resistant Ovarian Cancer. J Clin Oncol 2015; 33: 4015-4022 DOI: 10.1200/JCO.2015.62.3397.
- 124 Liu JF, Gordon M, Veneris J. et al. Safety, clinical activity and biomarker assessments of atezolizumab from a Phase I study in advanced/recurrent ovarian and uterine cancers. Gynecol Oncol 2019; 154: 314-322 DOI: 10.1016/j.ygyno.2019.05.021.
- 125 Matulonis UA, Shapira-Frommer R, Santin AD. et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol 2019; 30: 1080-1087 DOI: 10.1093/annonc/mdz135.
- 126 Matulonis U, Shapira R, Santin A. et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: Final results from the Phase 2 KEYNOTE-100 study. ASCO 2020. J Clin Oncol 2020; 38 (15_Suppl): 6005
- 127 Disis ML, Taylor MH, Kelly K. et al. Efficacy and Safety of Avelumab for Patients With Recurrent or Refractory Ovarian Cancer: Phase 1b Results From the JAVELIN Solid Tumor Trial. JAMA Oncol 2019; 5: 393-401 DOI: 10.1001/jamaoncol.2018.6258.
- 128 Motzer RJ, Escudier B, McDermott DF. et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373: 1803-1813 DOI: 10.1056/NEJMoa1510665.
- 129 Zorn KK, Bonome T, Gangi L. et al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res 2005; 11: 6422-6430 DOI: 10.1158/1078-0432.CCR-05-0508.
- 130 Howitt BE, Strickland KC, Sholl LM. et al. Clear cell ovarian cancers with microsatellite instability: A unique subset of ovarian cancers with increased tumor-infiltrating lymphocytes and PD-1/PD-L1 expression. Oncoimmunology 2017; 6: e1277308 DOI: 10.1080/2162402X.2016.1277308.
- 131 Färkkila A, Gulhan DC, Casado J. et al. Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer. Nat Commun 2020; 11: 1459 DOI: 10.1038/s41467-020-15315-8.
- 132 Coleman S, Clayton A, Mason MD. et al. Recovery of CD8+ T-cell function during systemic chemotherapy in advanced ovarian cancer. Cancer Res 2005; 65: 7000-7006 DOI: 10.1158/0008-5472.CAN-04-3792.
- 133 Ledermann JA, Colombo N, Oza AM. et al. Avelumab in combination with and/or following chemotherapy vs. chemotherapy alone in patients with previously untreated epithelial ovarian cancer: Results from the phase 3 javelin ovarian 100 trial. Gynecol Oncol 2020; 159: 13-14 DOI: 10.1016/j.ygyno.2020.06.025.
- 134 Ledermann JA. Avelumab in combination with and/or following chemotherapy vs. chemotherapy alone in patients with previously untreated epithelial ovarian cancer: Results from the phase 3 trial SGO-Meeting 2020. Gynecol Oncol 2020; 159 (Suppl. 01) 13-14 DOI: 10.1016/j.ygyno.2020.06.025.
- 135 Pujade-Lauraine E, Fujiwara K, Ledermann JA. et al. Avelumab alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in platinum-resistant or refractory epithelial ovarian cancer: Primary and biomarker analysis of the phase III JAVELIN Ovarian 200 trial. Gynecol Oncol 2019; 154: 21-22 DOI: 10.1016/j.ygyno.2019.04.053.
- 136 Pujade-Lauraine E. Avelumab alone or in combination with pegylated liposomal doxorubicin (PLD) vs. PLD alone in platinum-resistant or refractory epithelial ovarian cancer: primary and biomarker analysis of the phase 3 trial. SO Meeting 2019. Gynecol Oncol 2019; 154 (Suppl. 01) 21-22 DOI: 10.1016/j.ygyno.2019.04.053.
- 137 Stewart RA, Pilie PG, Yap TA. Development of PARP and Immune-Checkpoint Inhibitor Combinations. Cancer Res 2018; 78: 6717-6725 DOI: 10.1158/0008-5472.CAN-18-2652.
- 138 Peyraud F, Italiano A. Combined PARP Inhibition and Immune Checkpoint Therapy in Solid Tumors. Cancers (Basel) 2020; 12: 1502 DOI: 10.3390/cancers12061502.
- 139 Germano G, Lamba S, Rospo G. et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 2017; 552: 116-120 DOI: 10.1038/nature24673.
- 140 Mouw KW, Goldberg MS, Konstantinopoulos PA. et al. DNA Damage and Repair Biomarkers of Immunotherapy Response. Cancer Discov 2017; 7: 675-693 DOI: 10.1158/2159-8290.CD-17-0226.
- 141 Chabanon RM, Muirhead G, Krastev DB. et al. PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer. J Clin Invest 2019; 129: 1211-1228 DOI: 10.1172/JCI123319.
- 142 Ding L, Kim HJ, Wang Q. et al. PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer. Cell Rep 2018; 25: 2972-2980.e5 DOI: 10.1016/j.celrep.2018.11.054.
- 143 Pantelidou C, Sonzogni O, De Oliveria Taveira M. et al. PARP Inhibitor Efficacy Depends on CD8(+) T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer. Cancer Discov 2019; 9: 722-737 DOI: 10.1158/2159-8290.CD-18-1218.
- 144 Sen T, Rodriguez BL, Chen L. et al. Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer. Cancer Discov 2019; 9: 646-661 DOI: 10.1158/2159-8290.CD-18-1020.
- 145 Lee EK, Konstantinopoulos PA. PARP inhibition and immune modulation: scientific rationale and perspectives for the treatment of gynecologic cancers. Ther Adv Med Oncol 2020; 12: 1758835920944116 DOI: 10.1177/1758835920944116.
- 146 Zitvogel L, Galluzzi L, Kepp O. et al. Type I interferons in anticancer immunity. Nat Rev Immunol 2015; 15: 405-414 DOI: 10.1038/nri3845.
- 147 Mulligan AM, Raitman I, Feeley L. et al. Tumoral lymphocytic infiltration and expression of the chemokine CXCL10 in breast cancers from the Ontario Familial Breast Cancer Registry. Clin Cancer Res 2013; 19: 336-346
- 148 Mulligan JM, Hill LA, Deharo S. et al. Identification and validation of an anthracycline/cyclophosphamide-based chemotherapy response assay in breast cancer. J Natl Cancer Inst 2014; 106: djt335 DOI: 10.1093/jnci/djt335.
- 149 Parkes EE, Walker SM, Taggart LE. et al. Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer. J Natl Cancer Inst 2017; DOI: 10.1093/jnci/djw199.
- 150 Gao Y, Yang J, Cai Y. et al. IFN-gamma-mediated inhibition of lung cancer correlates with PD-L1 expression and is regulated by PI3K-AKT signaling. Int J Cancer 2018; 143: 931-943 DOI: 10.1002/ijc.31357.
- 151 Gottlieb CE, Mills AM, Cross JV. et al. Tumor-associated macrophage expression of PD-L1 in implants of high grade serous ovarian carcinoma: A comparison of matched primary and metastatic tumors. Gynecol Oncol 2017; 144: 607-612 DOI: 10.1016/j.ygyno.2016.12.021.
- 152 Jiao S, Xia W, Yamaguchi H. et al. PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression. Clin Cancer Res 2017; 23: 3711-3720 DOI: 10.1158/1078-0432.CCR-16-3215.
- 153 Sato H, Niimi A, Yasuhara T. et al. DNA double-strand break repair pathway regulates PD-L1 expression in cancer cells. Nat Commun 2017; 8: 1751 DOI: 10.1038/s41467-017-01883-9.
- 154 Wang Z, Sun K, Xiao Y. et al. Niraparib activates interferon signaling and potentiates anti-PD-1 antibody efficacy in tumor models. Sci Rep 2019; 9: 1853 DOI: 10.1038/s41598-019-38534-6.
- 155 Drew Y, Kaufman B, Banerjee S. et al. Phase II study of olaparib plus durvalumab (MEDIOLA): Updated results in germline BRCA-mutated platinum-sensitive relapsed (PSR) ovarian cancer (OC). Ann Oncol 2019; 30 (Suppl. 05) 1190PD
- 156 Drew Y, Penson RT, OʼMalley DM. et al. Phase II study of olaparib (O) plus durvalumab (D) and bevacizumab (B) (MEDIOLA): Initial results in patients (pts) with non-germline BRCA-mutated (non-gBRCAm) platinum sensitive relapsed (PSR) ovarian cancer (OC). Ann Oncol 2020; 31: S615-S616 DOI: 10.1016/j.annonc.2020.08.953.
- 157 Penson RT, Valencia RV, Cibula D. et al. Olaparib Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer and a Germline BRCA1/2 Mutation (SOLO3): A Randomized Phase III Trial. J Clin Oncol 2020; 38: 1164-1174 DOI: 10.1200/JCO.19.02745.
- 158 Drew Y. Phase II study of olaparib plus durvalumab and bevacizumab (MEDIOLA): initial results in patients with non-germline BRCA-mutated platinum sensitive relapsed ovarian cancer. ESMO 2020. Ann Oncol 2020; 31 (Suppl. 04) S615-S616 DOI: 10.1016/j.annonc.2020.08.953.
- 159 Gelmon KA, Tischkowitz M, Mackay H. et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 2011; 12: 852-861 DOI: 10.1016/S1470-2045(11)70214-5.
- 160 Sandhu SK, Schelman WR, Wilding G. et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol 2013; 14: 882-892 DOI: 10.1016/S1470-2045(13)70240-7.
- 161 Domchek SM, Aghajanian C, Shapira-Frommer R. 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. Gynecol Oncol 2016; 140: 199-203 DOI: 10.1016/j.ygyno.2015.12.020.
- 162 Oza AM, Tinker AV, Oaknin A. et al. Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2. Gynecol Oncol 2017; 147: 267-275 DOI: 10.1016/j.ygyno.2017.08.022.
- 163 Gulhan DC, Lee JJ, Melloni GEM. et al. Detecting the mutational signature of homologous recombination deficiency in clinical samples. Nat Genet 2019; 51: 912-919 DOI: 10.1038/s41588-019-0390-2.
- 164 Liu JF, Herold C, Gray KP. et al. Assessment of Combined Nivolumab and Bevacizumab in Relapsed Ovarian Cancer: A Phase 2 Clinical Trial. JAMA Oncol 2019; DOI: 10.1001/jamaoncol.2019.3343.
- 165 Pedersen M, Westergaard MCW, Milne K. et al. Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer: a pilot study. Oncoimmunology 2018; 7: e1502905 DOI: 10.1080/2162402X.2018.1502905.
- 166 Yan W, Hu H, Tang B. Advances Of Chimeric Antigen Receptor T Cell Therapy In Ovarian Cancer. Onco Targets Ther 2019; 12: 8015-8022 DOI: 10.2147/OTT.S203550.
- 167 Kverneland AH, Pedersen M, Westergaard MCW. et al. Adoptive cell therapy in combination with checkpoint inhibitors in ovarian cancer. Oncotarget 2020; 11: 2092-2105 DOI: 10.18632/oncotarget.27604.
- 168 Varga A, Piha-Paul S, Ott PA. et al. Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. Gynecol Oncol 2019; 152: 243-250 DOI: 10.1016/j.ygyno.2018.11.017.
- 169 Matulonis UA, Shapira R, Santin A. et al. Final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer. J Clin Oncol 2020; 38 (no. 15_suppl): 6005 DOI: 10.1200/JCO.2020.38.15_suppl.6005.