Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

doi:10.1001/jamaoncol.2017.3290

Multicenter Study

. 2017 Dec 1;3(12):e173290.

doi: 10.1001/jamaoncol.2017.3290.

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

Ovarian Tumor Tissue Analysis (OTTA) Consortium; Ellen L Goode¹, Matthew S Block², Kimberly R Kalli², Robert A Vierkant¹, Wenqian Chen³, Zachary C Fogarty¹, Aleksandra Gentry-Maharaj⁴, Aleksandra Tołoczko⁵, Alexander Hein⁶, Aliecia L Bouligny^{1

7}, Allan Jensen⁸, Ana Osorio^{9

10}, Andreas Hartkopf¹¹, Andy Ryan⁴, Anita Chudecka-Głaz¹², Anthony M Magliocco¹³, Arndt Hartmann¹⁴, Audrey Y Jung¹⁵, Bo Gao^{16

17}, Brenda Y Hernandez¹⁸, Brooke L Fridley¹⁹, Bryan M McCauley¹, Catherine J Kennedy^{16

20}, Chen Wang¹, Chloe Karpinskyj⁴, Christiani B de Sousa²¹, Daniel G Tiezzi²¹, David L Wachter¹⁴, Esther Herpel²², Florin Andrei Taran¹¹, Francesmary Modugno^{23

24

25}, Gregg Nelson²⁶, Jan Lubiński⁵, Janusz Menkiszak¹², Jennifer Alsop²⁷, Jenny Lester²⁸, Jesús García-Donas²⁹, Jill Nation²⁶, Jillian Hung^{16

20}, José Palacios³⁰, Joseph H Rothstein³¹, Joseph L Kelley²³, Jurandyr M de Andrade²¹, Luis Robles-Díaz³², Maria P Intermaggio³³, Martin Widschwendter⁴, Matthias W Beckmann⁶, Matthias Ruebner⁶, Mercedes Jimenez-Linan³⁴, Naveena Singh³⁵, Oleg Oszurek⁵, Paul R Harnett^{16

17}, Peter F Rambau^{3

36}, Peter Sinn³⁷, Philipp Wagner¹¹, Prafull Ghatage²⁶, Raghwa Sharma^{38

39}, Robert P Edwards²³, Roberta B Ness⁴⁰, Sandra Orsulic²⁸, Sara Y Brucker¹¹, Sharon E Johnatty⁴¹, Teri A Longacre⁴², Eilber Ursula¹⁵, Valerie McGuire⁴³, Weiva Sieh³¹, Yanina Natanzon¹, Zheng Li^{1

44}, Alice S Whittemore⁴⁵, deFazio Anna^{16

20}, Annette Staebler⁴⁶, Beth Y Karlan²⁸, Blake Gilks⁴⁷, David D Bowtell^{48

49

50}, Estrid Høgdall^{8

51}, Francisco J Candido dos Reis²¹, Helen Steed⁵², Ian G Campbell^{53

54

55}, Jacek Gronwald⁵, Javier Benítez^{9

10}, Jennifer M Koziak⁵⁶, Jenny Chang-Claude^{15

57}, Kirsten B Moysich⁵⁸, Linda E Kelemen⁵⁹, Linda S Cook⁶⁰, Marc T Goodman⁶¹, María José García^{9

10}, Peter A Fasching^{6

62}, Stefan Kommoss¹¹, Suha Deen⁶³, Susanne K Kjaer^{8

64}, Usha Menon⁴, James D Brenton^{65

66

67}, Paul DP Pharoah^{27

68}, Georgia Chenevix-Trench⁴¹, David G Huntsman^{69

70}, Stacey J Winham¹, Martin Köbel³, Susan J Ramus^{33

50}

Affiliations

¹ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
² Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
³ Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
⁴ Gynaecological Cancer Research Centre, Department of Women’s Cancer, Institute for Women’s Health, University College London, London, UK
⁵ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
⁶ Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg Comprehensive Cancer Center, Erlangen EMN, Germany
⁷ Department of Health Sciences, Spelman College, Atlanta, GA, USA
⁸ Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
⁹ Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
¹⁰ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
¹¹ Tübingen University Hospital, Department of Women’s Health, Tübingen, Germany
¹² Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland
¹³ Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL, USA
¹⁴ Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University
¹⁵ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
¹⁶ Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
¹⁷ The Crown Princess Mary Cancer Centre, Westmead Hospital, The University of Sydney, Australia
¹⁸ Cancer Center, University of Hawaii, Honolulu, HI, USA
¹⁹ Department of Biostatistics and Bioinformatics, Division of Population Sciences, Moffitt Cancer Center, Tampa, FL, USA
²⁰ Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
²¹ Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
²² Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Germany and Institute of Pathology, University of Heidelberg, Heidelberg, Germany
²³ Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
²⁴ Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA
²⁵ Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
²⁶ Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
²⁷ Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
²⁸ Women’s Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
²⁹ Medical Oncology Service, HM Hospitales – Centro Integral Oncológico HM Clara Campal, Madrid, Spain
³⁰ Pathology Department, Hospital Universitario Ramón y Cajal. IRYCIS. Universidad de Alcalá, Madrid, Spain. CIBERONC
³¹ Department of Population Health Science and Policy, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
³² Familial Cancer Unit and Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
³³ School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia
³⁴ Department of Histopathology, Addenbrookes Hospital, Cambridge, UK
³⁵ Department of Pathology, Barts Health National Health Service Trust, London, UK
³⁶ Pathology Department, Catholic University of Health and Allied Sciences-Bugando, Mwanza, Tanzania
³⁷ Department of Pathology, Institute of Pathology, Heidelberg University Hospital, Germany
³⁸ Pathology West ICPMR Westmead, Westmead Hospital, The University of Sydney, Sydney, Australia
³⁹ University of Western Sydney at Westmead Hospital, Westmead, New South Wales, Australia
⁴⁰ The University of Texas School of Public Health, Houston, TX, USA
⁴¹ Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
⁴² Department of Pathology, Stanford University, Stanford, CA, USA
⁴³ Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA
⁴⁴ Department of Gynecologic Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming, China
⁴⁵ Department of Health Research and Policy, Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA
⁴⁶ Tübingen University Hospital, Institute of Pathology, Tübingen, Germany
⁴⁷ Genetic Pathology Evaluation Centre, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia,Canada
⁴⁸ Cancer Genomics Program, Research Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
⁴⁹ Sir Peter MacCallum Department of Oncology, the University of Melbourne, Parkville, Victoria, Australia
⁵⁰ The Garvan Institute, Sydney, New South Wales, Australia
⁵¹ Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
⁵² Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Royal Alexandra Hospital, Edmonton, Alberta, Canada
⁵³ Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
⁵⁴ Sir Peter MacCallum Department of Oncology, University of Melbourne, Australia
⁵⁵ Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
⁵⁶ Alberta Health Services-Cancer Care, Calgary, Alberta, Canada
⁵⁷ University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
⁵⁸ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
⁵⁹ Department of Public Health Sciences, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC, USA
⁶⁰ Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, NM, USA
⁶¹ Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
⁶² David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, CA, USA
⁶³ Department of Histopathology, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
⁶⁴ Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
⁶⁵ Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK
⁶⁶ Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, UK
⁶⁷ Cambridge Experimental Cancer Medicine Centre, Cambridge, UK
⁶⁸ Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK
⁶⁹ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
⁷⁰ Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

PMID: 29049607
PMCID: PMC5744673
DOI: 10.1001/jamaoncol.2017.3290

Multicenter Study

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

Ovarian Tumor Tissue Analysis (OTTA) Consortium et al. JAMA Oncol. 2017.

. 2017 Dec 1;3(12):e173290.

doi: 10.1001/jamaoncol.2017.3290.

Authors

Affiliations

¹ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
² Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
³ Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
⁴ Gynaecological Cancer Research Centre, Department of Women’s Cancer, Institute for Women’s Health, University College London, London, UK
⁵ International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
⁶ Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg Comprehensive Cancer Center, Erlangen EMN, Germany
⁷ Department of Health Sciences, Spelman College, Atlanta, GA, USA
⁸ Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
⁹ Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
¹⁰ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
¹¹ Tübingen University Hospital, Department of Women’s Health, Tübingen, Germany
¹² Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland
¹³ Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL, USA
¹⁴ Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University
¹⁵ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
¹⁶ Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
¹⁷ The Crown Princess Mary Cancer Centre, Westmead Hospital, The University of Sydney, Australia
¹⁸ Cancer Center, University of Hawaii, Honolulu, HI, USA
¹⁹ Department of Biostatistics and Bioinformatics, Division of Population Sciences, Moffitt Cancer Center, Tampa, FL, USA
²⁰ Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
²¹ Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
²² Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Germany and Institute of Pathology, University of Heidelberg, Heidelberg, Germany
²³ Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
²⁴ Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA
²⁵ Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
²⁶ Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
²⁷ Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
²⁸ Women’s Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
²⁹ Medical Oncology Service, HM Hospitales – Centro Integral Oncológico HM Clara Campal, Madrid, Spain
³⁰ Pathology Department, Hospital Universitario Ramón y Cajal. IRYCIS. Universidad de Alcalá, Madrid, Spain. CIBERONC
³¹ Department of Population Health Science and Policy, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
³² Familial Cancer Unit and Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
³³ School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia
³⁴ Department of Histopathology, Addenbrookes Hospital, Cambridge, UK
³⁵ Department of Pathology, Barts Health National Health Service Trust, London, UK
³⁶ Pathology Department, Catholic University of Health and Allied Sciences-Bugando, Mwanza, Tanzania
³⁷ Department of Pathology, Institute of Pathology, Heidelberg University Hospital, Germany
³⁸ Pathology West ICPMR Westmead, Westmead Hospital, The University of Sydney, Sydney, Australia
³⁹ University of Western Sydney at Westmead Hospital, Westmead, New South Wales, Australia
⁴⁰ The University of Texas School of Public Health, Houston, TX, USA
⁴¹ Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
⁴² Department of Pathology, Stanford University, Stanford, CA, USA
⁴³ Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA
⁴⁴ Department of Gynecologic Oncology, The Third Affiliated Hospital of Kunming Medical University (Yunnan Tumor Hospital), Kunming, China
⁴⁵ Department of Health Research and Policy, Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA
⁴⁶ Tübingen University Hospital, Institute of Pathology, Tübingen, Germany
⁴⁷ Genetic Pathology Evaluation Centre, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia,Canada
⁴⁸ Cancer Genomics Program, Research Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
⁴⁹ Sir Peter MacCallum Department of Oncology, the University of Melbourne, Parkville, Victoria, Australia
⁵⁰ The Garvan Institute, Sydney, New South Wales, Australia
⁵¹ Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
⁵² Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Royal Alexandra Hospital, Edmonton, Alberta, Canada
⁵³ Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
⁵⁴ Sir Peter MacCallum Department of Oncology, University of Melbourne, Australia
⁵⁵ Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
⁵⁶ Alberta Health Services-Cancer Care, Calgary, Alberta, Canada
⁵⁷ University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
⁵⁸ Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
⁵⁹ Department of Public Health Sciences, Medical University of South Carolina and Hollings Cancer Center, Charleston, SC, USA
⁶⁰ Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, NM, USA
⁶¹ Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
⁶² David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, CA, USA
⁶³ Department of Histopathology, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
⁶⁴ Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
⁶⁵ Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, UK
⁶⁶ Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, UK
⁶⁷ Cambridge Experimental Cancer Medicine Centre, Cambridge, UK
⁶⁸ Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK
⁶⁹ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
⁷⁰ Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

PMID: 29049607
PMCID: PMC5744673
DOI: 10.1001/jamaoncol.2017.3290

Abstract

Importance: Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.

Objective: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer.

Design, setting, and participants: This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.

Exposures: Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.

Main outcomes and measures: Overall survival time.

Results: The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form.

Conclusions and relevance: This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bowtell receives funding from Astra Zeneca and Genentech Roche for the conduct of research studies and clinical trials unrelated to the work described in this article. Dr Huntsman is a founder and Chief Medical Officer of Contextual Genomics, a somatic mutation testing laboratory; the company’s work and interests do not overlap with the subject of and methodologies used in this manuscript. No other disclosures were reported.

Figures

**Figure. Kaplan-Meier Overall Survival Plots by CD8⁺ Tumor-Infiltrating Lymphocyte (TIL) Levels for the High-Grade Serous, Endometrioid, and Mucinous Ovarian Cancer**
Negative, no CD8⁺ TILs; low, 1–2 CD8⁺ TILs; moderate, 3–19 CD8⁺ TILs; high, 20 or more CD8⁺ TILs per high-powered field. The numbers just above the x-axis represent the number of women at risk in two year time intervals. Number at risk on date of diagnosis may be smaller than number at risk later due to left truncation of follow-up resulting from delayed study enrollment.

See this image and copyright information in PMC

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References

1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. - PubMed
1. 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(34):4015–4022. - PubMed
1. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–2465. - PMC - PubMed
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[1] Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. - PubMed

[2] Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. - PubMed

[3] 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(34):4015–4022. - PubMed

[4] 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(34):4015–4022. - PubMed

[5] Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–2465. - PMC - PubMed

[6] Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–2465. - PMC - PubMed

[7] 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(3):203–213. - PubMed

[8] 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(3):203–213. - PubMed

[9] Tomsova M, Melichar B, Sedlakova I, Steiner I. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma. Gynecol Oncol. 2008;108(2):415–420. - PubMed

[10] Tomsova M, Melichar B, Sedlakova I, Steiner I. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma. Gynecol Oncol. 2008;108(2):415–420. - PubMed

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Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

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Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

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