Clonal replacement of tumor-specific T cells following PD-1 blockade
| Autor: | Jeffrey M. Granja, Kavita Y. Sarin, Daniel K. Wells, Kathryn E. Yost, Chunlin Wang, Howard Y. Chang, Mark M. Davis, Ryanne A. Brown, Anne Lynn S. Chang, Yanyan Qi, Katherine McNamara, Christina Curtis, Rohit Gupta, Ansuman T. Satpathy, Samantha L. Bucktrout, Robin Kageyama |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment T cell Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Antigen Carcinoma medicine Basal cell carcinoma Receptor 030304 developmental biology 0303 health sciences T-cell receptor RNA General Medicine Immunotherapy medicine.disease Phenotype 3. Good health Blockade 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research CD8 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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