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Title:
Clonal replacement of tumor-specific T cells following PD-1 blockade | Nature Medicine
Description:
Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear2β4. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor. Following anti-PD-1 therapy in patients with basal or squamous cell carcinoma, the CD8+ T cell response largely consists of an expanded and exhausted repertoire of new T cell clones.
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nature portfolio journals permissions reprints nature portfolio privacy policy advertising vaccine research pd-1/pd-l1 blockade improves high-dimensional single-cell analysis social media south africa single-cell rna-seq data pre-existing tumor-infiltrating lymphocytes immune-cell-type clusters identified visualizing single-cell data high-fidelity hla genotyping nature+ nature 557 nature 564 nature 547 nature 537 nature 482 nature single-cell transcriptomic analysis scalable cloud-based platform tissue-resident memory subset tumor frequency/pbmc frequency single-cell rna-seq anti-pd-1 checkpoint blockade pre-existing tumor-infiltrating t-cell-dependent mechanism human tissue-resident memory pre-existing tumor-specific intratumoral tcf1+pd-1+cd8+ bulk rna-seq profiles bulk tcr-seq data pd-1βcd8+ tumor-infiltrating single-cell profiling permissions restore anti-tumor immunity anti-pd-1 treatment status stanford graduate fellowship squamous cell carcinoma squamous-cell carcinoma basal-cell carcinoma basal cell carcinoma post-pd-1 blockade colored springerlink instant access genomic analysis identifies previously published study6 previously published study21
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headline:Clonal replacement of tumor-specific T cells following PD-1 blockade
description:Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear2Γ’ΒΒ4. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor. Following anti-PD-1 therapy in patients with basal or squamous cell carcinoma, the CD8+ T cell response largely consists of an expanded and exhausted repertoire of new T cell clones.
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Cancer immunotherapy
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headline:Clonal replacement of tumor-specific T cells following PD-1 blockade
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