Clonal replacement of tumor-specific T cells following PD-1 blockade
Clonal replacement of tumor-specific T cells following PD-1 blockade
Abstract Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients. However, which tumor-specific T cells are mobilized following checkpoint blockade remains unclear. Here, we performed paired single-cell RNA- and T cell receptor (TCR)-sequencing on 79,046 cells from site-matched tumors from patients with basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) pre- and post-anti-PD-1 therapy. Tracking TCR clones and transcriptional phenotypes revealed a coupling of tumor-recognition, clonal expansion, and T cell dysfunction: the T cell response to treatment was accompanied by clonal expansions of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, this expansion did not derive from pre-existing tumor infiltrating T cell clones; rather, it comprised novel clonotypes, which were not previously observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells, compared to other distinct T cell phenotypes, and was evident in BCC and SCC patients. These results, enabled by single-cell multi-omic profiling of clinical samples, demonstrate that pre-existing tumor-specific T cells may be limited in their capacity for re-invigoration, and that the T cell response to checkpoint blockade relies on the expansion of a distinct repertoire of T cell clones that may have just recently entered the tumor.
Brown Ryanne A.、Curtis Christina、Bucktrout Samantha L.、Satpathy Ansuman T.、Wells Daniel K.、Wang Chunlin、Kageyama Robin、Sarin Kavita Y.、Chang Howard Y.、Granja Jeffrey M.、Qi Yanyan、McNamara Katherine、Yost Kathryn E.、Gupta Rohit K.、Davis Mark M.、Chang Anne Lynn S.
Department of Pathology, Stanford University School of Medicine||Department of Dermatology, Stanford University School of MedicineDepartment of Medicine, Division of Oncology, Stanford University School of Medicine||Department of Genetics, Stanford University School of Medicine||Stanford Cancer Institute, Stanford University School of MedicineParker Institute for Cancer ImmunotherapyCenter for Personal Dynamic Regulomes, Stanford University School of Medicine||Department of Pathology, Stanford University School of Medicine||Parker Institute for Cancer ImmunotherapyParker Institute for Cancer ImmunotherapyiRepertoire, IncParker Institute for Cancer ImmunotherapyDepartment of Dermatology, Stanford University School of MedicineCenter for Personal Dynamic Regulomes, Stanford University School of Medicine||Parker Institute for Cancer Immunotherapy||Department of Genetics, Stanford University School of Medicine||Department of Dermatology, Stanford University School of Medicine||Howard Hughes Medical Institute, Stanford University School of MedicineCenter for Personal Dynamic Regulomes, Stanford University School of Medicine||Department of Genetics, Stanford University School of Medicine||Program in Biophysics, Stanford University School of MedicineCenter for Personal Dynamic Regulomes, Stanford University School of MedicineDepartment of Medicine, Division of Oncology, Stanford University School of Medicine||Department of Genetics, Stanford University School of Medicine||Stanford Cancer Institute, Stanford University School of MedicineCenter for Personal Dynamic Regulomes, Stanford University School of MedicineStanford Biobank, Stanford University School of MedicineParker Institute for Cancer Immunotherapy||Department of Microbiology and Immunology, Stanford University School of Medicine||Institute for Immunity, Transplantation and Infection, Stanford University||Howard Hughes Medical Institute, Stanford University School of MedicineDepartment of Dermatology, Stanford University School of Medicine
肿瘤学医学研究方法基础医学
Brown Ryanne A.,Curtis Christina,Bucktrout Samantha L.,Satpathy Ansuman T.,Wells Daniel K.,Wang Chunlin,Kageyama Robin,Sarin Kavita Y.,Chang Howard Y.,Granja Jeffrey M.,Qi Yanyan,McNamara Katherine,Yost Kathryn E.,Gupta Rohit K.,Davis Mark M.,Chang Anne Lynn S..Clonal replacement of tumor-specific T cells following PD-1 blockade[EB/OL].(2025-03-28)[2025-06-13].https://www.biorxiv.org/content/10.1101/648899.点此复制
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