Relationship between T cell receptor clonotype and PD-1 expression of tumor-infiltrating lymphocytes in colorectal cancer

Adoptive T cell therapy using tumor-specific T cells or TCR-modified T cells is a promising next-generation immunotherapy. The major source of tumor-reactive T cells is PD-1(+) tumor-infiltrating lymphocytes (TILs). In contrast, PD-1(-) TILs have received little attention. Here, we analyzed the TCR-beta repertoires of PD-1(-) and PD-1(+) CD8(+) TILs derived from colorectal cancer and breast cancer. Approximately 40-60% of the PD-1(+) population consisted of oligoclonal populations in both colorectal cancer and breast cancer. In contrast, approximately 37% of the PD-1(-) population consisted of an oligoclonal population in colorectal cancer, whereas 14% of them were oligoclonal in breast cancer. In colorectal cancer, the TCR repertoires of PD-1(-)CD8(+) TILs and PD-1(+)CD8(+) TILs hardly overlapped. Interestingly, clonally expanded CD8(+) TILs in primary tumors and the metastases expressing the same clonotypic TCR showed the same phenotype regarding the PD-1-expression. These results suggest that the intrinsic properties of TCRs determine the fate of TILs in terms of whether they become PD-1(+) or PD-1(-) in the tumor microenvironment. Further functional analysis of TCRs in TILs will allow us to better understand the regulatory mechanisms for PD-1 expression on TILs and may contribute to tumor immunotherapy.