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Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell fate decisions by neoantigen-specific CD8+ T cells

ABSTRACT: Neoantigen-specific T cells specifically recognize tumor cells and are critical for cancer immunotherapies. However, the transcriptional program controlling the cell fate decisions by neoantigen-specific T cells is incompletely understood. Here, using joint single-cell transcriptome and TCR profiling, we mapped the clonal expansion and differentiation of neoantigen-specific CD8+ T cells in the tumor and draining lymph node in mouse prostate cancer. Compared to other antitumor CD8+ T cells and bystanders, neoantigen-specific CD8+ tumor-infiltrating T cells (TILs) upregulated gene signatures of T cell activation and exhaustion. In the tumor draining lymph node, we identified TCF1+TOX- TSCM, TCF1+TOX+ TPEX, and TCF1-TOX+ effector-like TEX subsets among neoantigen-specific CD8+ T cells. Clonal tracing analysis of neoantigen-specific CD8+ T cells revealed greater clonal expansion in divergent clones and less expansion in clones biased towards TEX, TPEX, or TSCM. The TPEX subset had greater 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 where neoantigen-specific clones exited the lymph node and differentiated into TEX TILs. Notably, TSCM differentiation of neoantigen-specific CD8+ clones in the lymph node 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 inhibitor. Together, we identified the transcriptional program that controls the cell fate choices by neoantigen-specific CD8+ T cells and correlates with clinical outcomes in cancer patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE290142 | GEO | 2025/10/06

REPOSITORIES: GEO

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Project description:Memory stem CD8 T cells (TSCM) are a long-lived T cell subset displaying stem cell-like properties, which play a significant role in anti-viral defense and exhibit a gene expression profile between naïve and central memory T cells. Yet, comprehensive transcriptional profiling of antigen-specific CD8 TSCM cells at the single cell level has not previously been undertaken. In this analysis, we utilized an in vitro single cell colony expansion protocol to study human CD8 T cell clones specific for Cytomegalovirus (CMV) epitopes - phenotypically, functionally, and in transcriptomes. We characterized clonal lineages from 3 donors by single cell sorting dextramer positive CD8 T cells of varied effector and memory surface phenotypes, all recognizing one of two HLA restricted CMV epitopes. Phenotypic and functional characterization of clonal lineages derived from antigen-specific TSCM revealed differentiated memory and effector subsets (TCM, TEM, TEFF) as well as TSCM, with the latter subset featuring multi-potentiality and multi-cytokine production. Studying TSCM-derived progeny of these varied differentiation phenotypes in single cell transcriptomic analysis revealed strong progenitor-to-progeny effects, whereby daughter cells from a shared progenitor clustered closely regardless of progeny differentiation phenotype, suggesting a dominant impact associated with heritable genes. The TSCM-derived TSCM-progeny revealed distinct transcriptomic profiles featuring expression of both recognized early differentiation memory T cell genes, such as IL7R, CCR7, SELL and CD27; as well as several novel genes which were shared across subjects and epitopes. The transcriptional features of clonal lineages are strongly dependent on the progenitor cell, but TSCM have an additional transcriptomic signature likely underpinning the unique differentiation and functional characteristics. These findings have important implications for identification of long-lived and multi-potent CD8 T cells for immunotherapy and immunization against viral infections.

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Single-cell clonal lineage tracing identifies the transcriptional program controlling the cell fate decisions by neoantigen-specific CD8+ T cells

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