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

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.

SUBMITTER: Tsuji T

PROVIDER: S-EPMC7343634 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Tsuji Takemasa T Eng Kevin H KH Matsuzaki Junko J Battaglia Sebastiano S Szender J Brian JB Miliotto Anthony A Gnjatic Sacha S Bshara Wiam W Morrison Carl D CD Lele Shashikant S Emerson Ryan O RO Wang Jianmin J Liu Song S Robins Harlan H Lugade Amit A AA Odunsi Kunle K

Oncotarget 20200707 27

CD8<sup>+</sup> 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 <i>de novo</i> assembly of sequences from CDR3 regions of 369 high-grade serous ovarian cancers from TCGA, and then applied deep TCR-sequencing for analyses o ...[more]

PMID: 32676168

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Project description:BackgroundTumor-infiltrating CD8+ T cells are correlated with prolonged progression-free and overall survival in epithelial ovarian cancer (EOC). A significant fraction of EOC patients mount autoantibody responses to various tumor antigens, however the relationship between autoantibodies and tumor-infiltrating T cells has not been investigated in EOC or any other human cancer. We hypothesized that autoantibody and T cell responses may be correlated in EOC and directed toward the same antigens.Methodology and principal findingsWe obtained matched serum and tumor tissue from 35 patients with high-grade serous ovarian cancer. Serum samples were assessed by ELISA for autoantibodies to the common tumor antigen NY-ESO-1. Tumor tissue was examined by immunohistochemistry for expression of NY-ESO-1, various T cell markers (CD3, CD4, CD8, CD25, FoxP3, TIA-1 and Granzyme B) and other immunological markers (CD20, MHC class I and MHC class II). Lymphocytic infiltrates varied widely among tumors and included cells positive for CD3, CD8, TIA-1, CD25, FoxP3 and CD4. Twenty-six percent (9/35) of patients demonstrated serum IgG autoantibodies to NY-ESO-1, which were positively correlated with expression of NY-ESO-1 antigen by tumor cells (r = 0.57, p = 0.0004). Autoantibodies to NY-ESO-1 were associated with increased tumor-infiltrating CD8+, CD4+ and FoxP3+ cells. In an individual HLA-A2+ patient with autoantibodies to NY-ESO-1, CD8+ T cells isolated from solid tumor and ascites were reactive to NY-ESO-1 by IFN-gamma ELISPOT and MHC class I pentamer staining.Conclusion and significanceWe demonstrate that tumor-specific autoantibodies and tumor-infiltrating T cells are correlated in human cancer and can be directed against the same target antigen. This implies that autoantibodies may collaborate with tumor-infiltrating T cells to influence clinical outcomes in EOC. Furthermore, serological screening methods may prove useful for identifying clinically relevant T cell antigens for immunotherapy.

Dataset Information

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

Publications

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

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