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

Abstract

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-β 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.

Keywords: PD-1; TCR; TIL; colorectal cancer; repertoire.