Single-cell analysis reveals clonally expanded tumor-associated CD57+ CD8 T cells are enriched in the periphery of patients with metastatic urothelial cancer responding to PD-L1 blockade

阿替唑单抗 CD8型 细胞毒性T细胞 T细胞 癌症研究 免疫检查点 T细胞受体 免疫系统 医学 免疫学 生物 免疫疗法 无容量 体外 生物化学
作者
Michael Fehlings,Leesun Kim,Xiangnan Guan,Kobe Yuen,Alireza Tafazzol,Shomyseh Sanjabi,Oliver A. Zill,Deepali Rishipathak,Andrew Wallace,Alessandra Nardin,Siming Ma,Ana Milojkovic,Evan W. Newell,Sanjeev Mariathasan,Mahesh Yadav
出处
期刊:Journal for ImmunoTherapy of Cancer [BMJ]
卷期号:10 (8): e004759-e004759 被引量:23
标识
DOI:10.1136/jitc-2022-004759
摘要

Background A growing body of evidence suggests that T-cell responses against neoantigens are critical regulators of response to immune checkpoint blockade. We previously showed that circulating neoantigen-specific CD8 T cells in patients with lung cancer responding to anti-Programmed death-ligand 1 (PD-L1) (atezolizumab) exhibit a unique phenotype with high expression of CD57, CD244, and KLRG1. Here, we extended our analysis on neoantigen-specific CD8 T cells to patients with metastatic urothelial cancer (mUC) and further profiled total CD8 T cells to identify blood-based predictive biomarkers of response to atezolizumab. Methods We identified tumor neoantigens from 20 patients with mUC and profiled their peripheral CD8 T cells using highly multiplexed combinatorial tetramer staining. Another set of patients with mUC treated with atezolizumab (n=30) or chemotherapy (n=40) were selected to profile peripheral CD8 T cells by mass cytometry. Using single-cell transcriptional analysis (single-cell RNA sequencing (scRNA-seq)), together with CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) and paired T-cell receptor (TCR) sequencing, we further characterized peripheral CD8 T cells in a subset of patients (n=16). Results High frequency of CD57 was observed in neoantigen-specific CD8 T cells in patients with mUC responding to atezolizumab. Extending these findings to bulk CD8 T cells, we found higher frequency of CD57 expressing CD8 T cells before treatment in patients responding to atezolizumab (n=20, p<0.01) but not to chemotherapy. These findings were corroborated in a validation cohort (n=30, p<0.01) and notably were independent of known biomarkers of response. scRNA-seq analysis identified a clonally expanded cluster enriched within CD57 + CD8 T cells in responding patients characterized by higher expression of genes associated with activation, cytotoxicity, and tissue-resident memory markers. Furthermore, compared with CD57 − CD8 T cells, TCRs of CD57 + CD8 T cells showed increased overlap with the TCR repertoire of tumor-infiltrating T cells. Conclusions Collectively, we show high frequencies of CD57 among neoantigen-specific and bulk CD8 T cells in patients responding to atezolizumab. The TCR repertoire overlap between peripheral CD57 + CD8 T cells and tumor-infiltrating lymphocytes suggest that accumulation of peripheral CD57 + CD8 T cells is reflective of an ongoing antitumor T-cell response. Our findings provide evidence and rationale for using circulating CD8 T cells expressing CD57 as a readily accessible blood-based biomarker for selecting patients with mUC for atezolizumab therapy.
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