Clonality and antigen-specific responses shape the prognostic effects of tumor-infiltrating T cells in ovarian cancer

Takemasa Tsuji, Kevin H. Eng, Junko Matsuzaki, Sebastiano Battaglia, J. Brian Szender, Anthony Miliotto, Sacha Gnjatic, Wiam Bshara, Carl D. Morrison, Shashikant Lele, Ryan O. Emerson, Jianmin Wang, Song Liu, Harlan Robins, Amit A. Lugade, Kunle Odunsi

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

CD8+ tumor-infiltrating lymphocytes (TILs) are not all specific for tumor antigens, but can include bystander TILs that are specific for cancer-irrelevant epitopes, and it is unknown whether the T-cell repertoire affects prognosis. To delineate the complexity of anti-tumor T-cell responses, we utilized a computational method for de novo assembly of sequences from CDR3 regions of 369 high-grade serous ovarian cancers from TCGA, and then applied deep TCR-sequencing for analyses of paired tumor and peripheral blood specimens from an independent cohort of 99 ovarian cancer patients. Strongly monoclonal T-cell repertoires were associated with favorable prognosis (PFS, HR = 0.65, 0.50-0.84, p = 0.003; OS, HR = 0.61, 0.44-0.83, p = 0.006) in TCGA cohort. In the validation cohort, we discovered that patients with low T-cell infiltration but low diversity or focused repertoires had clinical outcomes almost indistinguishable from highly-infiltrated tumors (median 21.0 months versus 15.9 months, log-rank p = 0.945). We also found that the degree of divergence of the peripheral repertoire from the TIL repertoire, and the presence of detectable spontaneous anti-tumor immune responses are important determinants of clinical outcome. We conclude that the prognostic significance of TILs in ovarian cancer is dictated by T-cell clonality, degree of overlap with peripheral repertoire, and the presence of detectable spontaneous anti-tumor immune response in the patients. These immunological phenotypes defined by the TCR repertoire may provide useful insights for identifying “TIL-low” ovarian cancer patients that may respond to immunotherapy.

Original languageEnglish
Pages (from-to)2669-2683
Number of pages15
JournalOncotarget
Volume11
Issue number27
DOIs
StatePublished - 1 Jul 2020

Keywords

  • Ovarian cancer
  • T-cell repertoire
  • Tumor immunity

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