Clinical and immunological response to checkpoint therapy in renal cell carcinoma is associated with TCF1+ CD8 T-cells in the tumor

We investigated changes in T cell responses in the peripheral blood of patients with advanced renal cell carcinoma (RCC) after receiving immunotherapy. We found that a small proportion of both CD4 and CD8 cells activate and express the proliferation marker Ki67 and the activation markers HLA-DR and CD38. Patients who had the highest increase in these HLA-DR+CD38+ CD8 T cells after treatment had the best anti-tumor response. We studied these newly activated cells in more detail using flow cytometry and RNAseq and found that while these cells expanded in most patients, their phenotype did not drastically change during treatment. However, when we analyzed the TCR repertoire of these HLA-DR+CD38+CD8+ T cells, we found only patients who responded to the treatment had a burst of new clonotypes enter this pool of activated cells. Finally, we investigated how the T-cell response in the resected tumor months or years before receiving checkpoint therapy predicted later response to checkpoint therapy. Together, these data suggest that having a strong pre-existing immune response and immediate T cell response to checkpoint therapy is a predictor of anti-tumor response in patients with RCC.