Clonal spreading of tumor-infiltrating T cells underlies the robust antitumor immune responses

Abstract

The repertoire of tumor-infiltrating T cells is an emerging perspective for characterizing effective antitumor T-cell responses. Oligoclonal expansion of tumor T-cell repertoire has been evaluated; however, their association with antitumor effects is unclear. We demonstrated that the polyclonal fraction of the tumor-reactive T-cell repertoire consisting of relatively minor clones increased in tumor-bearing mice treated with anti-PD-L1 or anti-CD4 monoclonal antibody, which was correlated with antitumor effect. Meanwhile, the size of the oligoclonal fraction consisting of major clones remained unchanged. Moreover, the polyclonal fraction was enriched in progenitor exhausted T cells, which are essential for a durable antitumor response, and was more dependent on CCR7⁺ migratory dendritic cells, which are responsible for priming tumor-reactive T cells in the tumor-draining lymph nodes. These results suggest that the expansion of diverse tumor-reactive clones (“clonal spreading”) is an important mechanism by which anti-PD-L1 and anti-CD4 treatments induce robust and durable antitumor T-cell responses.