Clonal spreading of tumor-infiltrating T cells underlies the durable antitumor effects of PD-1 blockade and anti-CD4 monoclonal antibody: Bulk TCR sequencing
The repertoire of tumor-infiltrating T cells is a novel perspective to characterize effective anti-tumor T cell responses. Previous studies reported that the oligoclonal expansion in tumor T-cell repertoire is associated with anti-tumor effects. However, the contribution of the expansion of diverse T-cell clones remained unclear. We demonstrated that the polyclonal fraction of tumor-reactive T-cell repertoire consisting of relatively minor clones, increased in tumor-bearing mice treated with anti-PD-L1 or anti-CD4 monoclonal antibodies (mAbs), while the oligoclonal fraction consisting of major clones was unchanged. Moreover, the polyclonal fraction was enriched with progenitor exhausted T cells, essential for a durable anti-tumor response, and more dependent on CCR7+ migratory dendritic cells, responsible for priming tumor-reactive T cells in the tumor-draining lymph node (dLN). These results proposed that the expansion of diverse tumor-reactive clones, “clonal spreading,” is an important mechanism by which anti-PD-L1 and anti-CD4 treatments exert robust and durable anti-tumor T-cell responses.
Overall design
CD8+ PD1-, CD8+ PD1+ Ly108+ Tim3-, CD8+ PD1+ Ly108+ Tim3+, and CD8+ PD1+ Ly108- Tim3+ T cells from tumor, and CD8+ CD44high T cells from dLN were collected from B16F10 tumor-bearing mouse treated with anti-CD4 mAb, anti-PD-L1 mAb or combination of anti-CD4 and anti-PD-L1 mAbs. Bulk TCR sequencing was performed, and T cell clones that overlap between tumor and dLN were identified.
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