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.
Highlights
Whereas the Cancer Genome Atlas (TCGA) cohort was restricted to highgrade serous histotype, patients with non-serous tumors were included in the Roswell Park Cancer Institute (RPCI) cohort because of availability of paired peripheral blood mononuclear cell (PBMC) and tumor specimens
These results indicate that the expression of cancer testis (CT) antigens, when accompanied by high tumor infiltrating lymphocyte (TIL), produces an immunogenic tumor microenvironment that is associated with improved progression-free survival (PFS) and overall survival (OS) in ovarian cancer patients
Summary features of the TIL repertoire were strongly associated with prognosis in TCGA cohort (Supplementary Table 1)
Summary
The presence of tumor-infiltrating lymphocytes (TILs) is a key determinant of clinical outcome in a wide range of solid tumors including ovarian cancer [1,2,3,4,5]. previous studies have identified additional parameters that associate with effective anti-tumor immunity, such as the differentiation state of TILs [2, 4], the ratio of effector to immunosuppressive cells [1, 5, 6], and tumor production of immune inhibitory molecules www.oncotarget.com [7], these do not fully explain the varied and dynamic range of immune components influencing prognosis. The random addition and deletion of nucleotides during T cell receptor (TCR) recombination in the complementarity-determining region 3 (CDR3) provides variation in TCR sequences that is shaped further by selection and clonal expansion following exposure to immunogenic antigens. In this regard, characterizing the specific type and number of TCR clonotypes deployed to engage tumor antigens both at the tumor site and in the periphery may provide unique qualitative insights into the nature of the antitumor response required for clinical benefit. Immunotherapy trials in melanoma and pancreatic cancer patients have demonstrated the potential for TCR repertoire profiling to serve as a biomarker of clinical response and toxicity [21, 22]
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