Clonality and antigen-specific responses shape the prognostic effects of tumor-infiltrating T cells in ovarian cancer
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Takemasa Tsuji1,*, Kevin H. Eng2,3,*, Junko Matsuzaki1, Sebastiano Battaglia1, J. Brian Szender4, Anthony Miliotto1, Sacha Gnjatic5, Wiam Bshara6, Carl D. Morrison6, Shashikant Lele4, Ryan O. Emerson7, Jianmin Wang2, Song Liu2, Harlan Robins7, Amit A. Lugade1 and Kunle Odunsi1,4
1 Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
2 Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
3 Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
4 Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
5 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
6 Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
7 Adaptive Biotechnologies, Seattle, WA, USA
* These authors contributed equally to this work
Keywords: T-cell repertoire; ovarian cancer; tumor immunity
Received: April 18, 2020 Accepted: June 15, 2020 Published: July 07, 2020
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.
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