Article open access publication

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

JAMA Oncology, American Medical Association (AMA), ISSN 2374-2445

Volume 3, 12, 2017

DOI:10.1001/jamaoncol.2017.3290, Dimensions: pub.1092290657, PMC: PMC5744673, PMID: 29049607,


Osorio, Ana (8) (9)
Gao, Bo (14) (15)
Herpel, Esther (19) (20)
Hung, Jillian (14) (17)
Harnett, Paul R (14) (15)
Rambau, Peter F. (2) (32)
Sharma, Raghwa (34) (35)
Li, Zheng (1) (39)
deFazio, Anna (14) (17)
Bowtell, David D L (41) (42) (43)
Høgdall, Estrid (7) (44)
Campbell, Ian G (41) (42)
Deen, Suha (52)
Brenton, James D. (23) (54) (55)
Huntsman, David G. (40) (56)
Ramus, Susan J (29) (43)



  1. (1) Mayo Clinic, grid.66875.3a
  2. (2) University of Calgary, grid.22072.35
  3. (3) University College London, grid.83440.3b
  4. (4) Pomeranian Medical University, grid.107950.a
  5. (5) Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nuremberg Comprehensive Cancer Center, Erlangen EMN, Germany
  6. (6) Spelman College, grid.263934.9
  7. (7) Danish Cancer Society, grid.417390.8
  8. (8) Institute of Health Carlos III, grid.413448.e
  9. (9) Spanish National Cancer Research Centre, grid.7719.8
  10. (10) Universitätsklinikum Tübingen, grid.411544.1
  11. (11) Moffitt Cancer Center, grid.468198.a
  12. (12) Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  13. (13) German Cancer Research Center, grid.7497.d
  14. (14) University of Sydney, grid.1013.3
  15. (15) The Crown Princess Mary Cancer Centre, Westmead Hospital, The University of Sydney, Australia
  16. (16) University of Hawaii at Manoa, grid.410445.0
  17. (17) Westmead Hospital, grid.413252.3
  18. (18) University of Sao Paulo, grid.11899.38
  19. (19) Heidelberg University, grid.7700.0
  20. (20) National Center for Tumor Diseases, grid.461742.2
  21. (21) University of Pittsburgh Cancer Institute, grid.478063.e
  22. (22) University of Pittsburgh, grid.21925.3d
  23. (23) University of Cambridge, grid.5335.0
  24. (24) Cedars-Sinai Medical Center, grid.50956.3f
  25. (25) Medical Oncology Service, HM Hospitales–Centro Integral Oncológico HM Clara Campal, Madrid, Spain
  26. (26) Hospital Universitario Ramón y Cajal, grid.411347.4
  27. (27) Icahn School of Medicine at Mount Sinai, grid.59734.3c
  28. (28) Hospital Universitario 12 De Octubre, grid.144756.5
  29. (29) UNSW Sydney, grid.1005.4
  30. (30) Addenbrooke's Hospital, grid.120073.7
  31. (31) Department of Pathology, Barts Health National Health Service Trust, London, England
  32. (32) Catholic University of Health and Allied Sciences, grid.411961.a
  33. (33) Department of Pathology, Institute of Pathology, Heidelberg University Hospital, Germany
  34. (34) Pathology West ICPMR Westmead, Westmead Hospital, The University of Sydney, Sydney, Australia
  35. (35) Western Sydney University, grid.1029.a
  36. (36) The University of Texas Health Science Center at Houston, grid.267308.8
  37. (37) QIMR Berghofer Medical Research Institute, grid.1049.c
  38. (38) Stanford University, grid.168010.e
  39. (39) Yan'an Hospital Affiliated To Kunming Medical University, grid.452826.f
  40. (40) University of British Columbia, grid.17091.3e
  41. (41) Peter MacCallum Cancer Centre, grid.1055.1
  42. (42) University of Melbourne, grid.1008.9
  43. (43) Garvan Institute of Medical Research, grid.415306.5
  44. (44) University of Copenhagen, grid.5254.6, KU
  45. (45) Royal Alexandra Hospital, grid.416087.c
  46. (46) Alberta Health Services, grid.413574.0
  47. (47) University Cancer Center Hamburg, grid.412315.0
  48. (48) Roswell Park Cancer Institute, grid.240614.5
  49. (49) Hollings Cancer Center, grid.467988.c
  50. (50) University of New Mexico, grid.266832.b
  51. (51) David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles
  52. (52) Queen's Medical Centre, grid.415598.4
  53. (53) Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  54. (54) Cambridge Experimental Cancer Medicine Centre, Cambridge, England
  55. (55) Cancer Research UK Cambridge Institute, grid.470869.4
  56. (56) BC Cancer Agency, grid.248762.d


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.


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