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Elucidating cellular states of CD8+ T cells regulating anti-tumor response using multi-omic single cell sequencing

ABSTRACT: Immune checkpoint blockade (ICB) has led to durable clinical responses in multiple cancer types; however, biomarkers that identify which patients are most likely to respond to ICB are not well defined. Many putative biomarkers developed from a small number of samples often fail to maintain their predictive status in larger validation cohorts. We show across multiple human malignancies and syngeneic murine tumor models that neither pre-treatment T cell receptor (TCR) clonality nor changes in clonality after ICB correlate with response. Dissection of tumor infiltrating lymphocytes pre- and post-ICB by paired single-cell RNA sequencing and single-cell TCR sequencing reveals conserved and distinct transcriptomic features in expanded TCR clonotypes between anti-PD1 responder and non-responder murine tumor models. Overall, our results indicate a productive anti-tumor response is agnostic of TCR clonal expansion. Further, we used single-cell transcriptomics to develop a CD8+ T cell specific gene signature for a productive anti-tumor response and show the response signature to be associated with clinical outcomes to nivolumab monotherapy in CheckMate-067, a phase 3 clinical trial in metastatic melanoma. These results highlight the value of leveraging single-cell assays to dissect heterogeneous tumors and T cell subsets and define cell-type specific transcriptomic biomarkers of ICB response.

ORGANISM(S): Mus musculus

PROVIDER: GSE191129 | GEO | 2022/07/14

REPOSITORIES: GEO

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