Daunorubicin-induced T cell remodeling facilitates a high antitumor response to PD-1 blockade therapy by promoting the expansion and effector function of CD8+ prolifeating T cells [scRNA-Seq]

We showed that chemotherapy agent doxorubicin-pretreated CD8+ proliferating T cells had enhanced cytolytic activity against tumors after anti-PD-1 treatment in vitro. Doxorubicin-plus-anti-PD-1 treatment promoted the activation and expansion of endogenous tumor-reactive CD8+ proliferating T cells and efficiently suppressed tumor growth in multiple mice tumor models. The single-cell RNA-sequencing and TCR-sequencing demonstrated that doxorubicin-plus-anti-PD-1 combination altered the metabolic reprogramming and activation of CD8+ proliferating T cells and markedly elevated the clonally expansion and effector function of proliferating T cells as compared with anti-PD-1 monotherapy, presenting increased expression of genes associated with T cell activation, proliferation, cytolytic activity, memory and mitochondrial metabolism. Strikingly, doxorubicin-plus-anti-PD-1 combination promoted the expression and activity of T cell activation transcription factor Nfat, which was reduced following PD-1 blockade therapy. Together, our findings show that the novel chemoimmunotherapy remodels CD8+ proliferating T subset, improves responsiveness to anti-PD-1 therapy.