Concurrent delivery of immune checkpoint blockade modulates T cell dynamics to enhance neoantigen vaccine-generated anti-tumor immunity

Neoantigen vaccines aiming to induce tumor-specific T cell responses have achieved promising anti-tumor effects in early clinical trials. However, the underlying mechanism regarding response or resistance to this treatment remains unclear. Here, we observe that neoantigen vaccine-generated T cells can synergize with immune checkpoint blockade (ICB) for effective tumor control. Specifically, we performed single-cell sequencing on over 100,000 T cells and uncovered that combined therapy induces an antigen-specific CD8 T cell population with active chemokine signaling (Cxcr3(+)/Ccl5(+)), lower co-inhibitory receptor expression (Lag3(−)/Havcr2(−)) and higher cytotoxicity (Fasl(+)/Gzma(+)). Furthermore, the generation of neoantigen-specific T cells in the draining lymph node is required for combination treatment. Signature genes of this unique population are associated with T cell clonal frequency and better survival in humans. Our study profiles the dynamics of tumor infiltrated T cells during neoantigen vaccine and ICB treatments, high-dimensionally identifies neoantigen-reactive T cell signatures for future development of therapeutic strategies.