A minority of T cells recognizing tumor-associated antigens presented in self-HLA can provoke antitumor reactivity

Tumor-associated antigens (TAAs) 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 cellswere used as a model, as the influence of thymic selection on the T-cell repertoire directed against MiHA can be studied in both self (MiHA(pos) donors) and non-self (MiHA(neg) donors) backgrounds. T-cell clones directed against the HLA*02:01-restricted MiHA HA-1H were isolated from HA-1H(neg)/HLA-A*02:01(pos) and HA1H(pos)/HLA-A*02:01(pos) donors. Of the 16 uniqueHA-1H-specificT-cell clones, five T-cell clones derived from HA-1H(neg)/HLA-A*02:01(pos) donors and one T-cell clone derived from an HA1H(pos)/HLA-A*02:01(pos) donor showed reactivity against HA-1H(pos) target cells. In addition, 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*02:01(pos) donors. Only 3 PRAME-VLD-specific and one NY-eso-1-SLL-specific T-cell clone provoked interferon-g production and/or cytolysis upon stimulation with HLA-A*02:01(pos) malignant cell lines (but not primary malignant samples) naturally overexpressing the TAA. These results show that self-HLA-restricted T cells specific for selfantigens such as MiHA in MiHA(pos) donors and TAAs are present in peripheral blood of healthy individuals. However, 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. (Blood. 2020;136(4):455-467)Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease