A Minority of T Cells Recognizing Tumor-Associated Antigens Presented in Self-HLA Can Provoke Anti-Tumor Reactivity.

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Tumor-associated antigens (TAA) are monomorphic self-antigens that are proposed as targets for immunotherapeutic approaches to treat malignancies. We investigated whether T cells with sufficient avidity to recognize naturally overexpressed self-antigens in the context of self-HLA can be found in the T-cell repertoire of healthy donors. Minor histocompatibility antigen (MiHA)-specific T cells were used as model, as the influence of thymic selection on the T-cell repertoire directed against MiHA can be studied in both self (MiHApos donors)and non-self (MiHAneg donors) backgrounds. T-cell clones directed against the HLA*02:01-restricted MiHA HA-1H were isolated from HA-1Hneg/HLA-A*02:01pos and HA-1Hpos/HLA-A*02:01pos donors. Of the 16 unique HA-1H-specific T-cell clones, 5 T-cell clones derived from HA-1Hneg/HLA-A*02:01pos donors and 1 T-cell clone derived from an HA-1Hpos/HLA-A*02:01pos donor showed reactivity against HA-1Hpos target cells. Additionally, in total 663 T-cell clones (containing at least 91 unique clones expressing different T-cell receptors) directed against HLA*02:01-restricted peptides of TAA WT1-RMF, RHAMM-ILS, Proteinase-3-VLQ, PRAME-VLD and NY-eso-1-SLL were isolated from HLA-A*02:01pos donors. Only 3 PRAME-VLD- and 1 NY-eso-1-SLL-specific T-cell clone provoked IFN-gamma production and/or cytolysis upon stimulation with HLA-A*02:01pos malignant cell lines (but not primary malignant samples) naturally overexpressing the TAA. These results illustrate that self-HLA-restricted T cells specific for self-antigens like MiHA in MiHApos donors and TAA are present in peripheral blood of healthy individuals, but clinical efficacy would require highly effective in-vivo priming by peptide vaccination in the presence of proper adjuvants or in-vitro expansion of the low numbers of self-antigen-specific T cells of sufficient avidity to recognize endogenously processed antigen. T-cell clones directed against the HLA*02:01-restricted MiHA HA-1H were isolated from HA-1Hneg/HLA-A*02:01pos and HA-1Hpos/HLA-A*02:01pos donors. Of the 16 unique HA-1H-specific T-cell clones, 5 T-cell clones derived from HA-1Hneg/HLA-A*02:01pos donors and 1 T-cell clone derived from an HA-1Hpos/HLA-A*02:01pos donor showed reactivity against HA-1Hpos target cells. Additionally, in total 663 T-cell clones (containing at least 91 unique clones expressing different T-cell receptors) directed against HLA*02:01-restricted peptides of TAA WT1-RMF, RHAMM-ILS, Proteinase-3-VLQ, PRAME-VLD and NY-eso-1-SLL were isolated from HLA-A*02:01pos donors. Only 3 PRAME-VLD- and 1 NY-eso-1-SLL-specific T-cell clone provoked IFN-gamma production and/or cytolysis upon stimulation with HLA-A*02:01pos malignant cell lines (but not primary malignant samples) naturally overexpressing the TAA. These results illustrate that self-HLA-restricted T cells specific for self-antigens like MiHA in MiHApos donors and TAA are present in peripheral blood of healthy individuals, but clinical efficacy would require highly effective in-vivo priming by peptide vaccination in the presence of proper adjuvants or in-vitro expansion of the low numbers of self-antigen-specific T cells of sufficient avidity to recognize endogenously processed antigen.


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