单细胞克隆谱系追踪鉴定控制新抗原特异性 CD8+ T 细胞细胞命运决定的转录程序

Neoantigen-specific T cells recognize tumor cells and are critical for cancer immunotherapies to be effective.

However, the transcriptional program controlling the cell fate decisions by neoantigen-specific T cells is incompletely understood. In this study, using joint single-cell transcriptome and T-cell receptor profiling, we mapped the clonal expansion and differentiation of neoantigen-specific CD8+ T cells in the tumor and draining lymph node (LN) in mouse prostate cancer. Neoantigen-specific CD8+ tumor-infiltrating lymphocytes upregulated gene signatures of T-cell activation and exhaustion compared with those recognizing other tumor antigens. In the tumor-draining LN, we identified TCF1+TOX- stem cell memory T cells (TSCM), TCF1+TOX+ progenitor exhausted T cells (TPEX), and TCF1-TOX+ effector-like exhausted CD8+ T cells (TEX) subsets among neoantigen-specific CD8+ T cells.

Divergent neoantigen-specific CD8+ T-cell clones with balanced distribution across multiple differentiation fates underwent significantly greater expansion compared with clones biased toward TEX, TPEX, or TSCM.

The TPEX subset had the greatest clonal diversity and likely represented the root of neoantigen-specific CD8+ T-cell differentiation, whereas highly clonally expanded effector-like TEX cells were positioned at the branch point in which neoantigen-specific clones exited the LN and differentiated into TEX tumor-infiltrating lymphocytes. TSCM differentiation of neoantigen-specific CD8+ T-cell clones in the LN negatively correlated with exhaustion and clonal expansion of the same clones in the tumor.

In addition, the gene signature of neoantigen-specific clones biased toward tumor infiltration relative to lymph node residence predicted a poorer response to immune checkpoint inhibitors by patients with cancer.

In conclusion, we have identified a transcriptional program that controls the cell fate choices by neoantigen-specific CD8+ T cells and correlates with clinical outcomes in patients with cancer.