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

Abstract

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.

T cell receptor convergence is an indicator of antigen-specific T cell response in cancer immunotherapies

“…(Each cell type corresponds to the following clusters in the original paper: T.na: CD8-04-Ccr7; T.eff: CD8-05-Fasl; T.rm: CD8-06-Xcl1; T.ex: CD8-08-Lag3. (L. Liu et al, 2022)) Each dot represents a T cell.…”

“…The first dataset we investigated contained tetramer-labeled neoantigen-specific T cells in the MC38 tumor mouse model treated with neoantigen vaccine and anti-PD-L1 (Longchao Liu et al, 2022). The CD4 + and CD8 + T cells were analyzed separately using the same cell cluster annotations as previously described (Longchao Liu et al, 2022). We then defined and analyzed the convergent TCRs using the scTCR-seq data of the same T cells.…”

“…(Each cell type corresponds to the following clusters in the original paper: T.na: CD8-04-Ccr7; T.eff: CD8-05-Fasl; T.rm: CD8-06-Xcl1; T.ex: CD8-08-Lag3. (L. Liu et al, 2022)) Each dot represents a T cell. The area within the red dashed line indicates enrichment of convergent T cells and cells within the blue dashed line were naive T cells.…”

“…Cell type annotations and convergent T cell distribution of CD4 + T cells collected from mouse tumor tissues. (Each cell type corresponds to the following clusters in the original paper: T.na: CD4-04-S1pr1; T.Treg: CD4-05- Ctla4; T.Th1: CD4-06-Bhlhe40; T.rTreg: CD4-07-Ccr5 (L. Liu et al, 2022)).…”

“…Over the last few years, high-throughput bulk TCRβ-sequencing (bulk TCR-seq) and single-cell immune profiling have become powerful tools for unraveling a variety of biological problems (Longchao Liu et al, 2022; Zheng et al, 2017). Previously generated datasets are excellent resources for re-analysis.…”