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Clonal replacement of tumor-specific T cells following PD-1 blockade

Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients(1). However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor infiltrating T cells (TILs) or on recruitment of novel T cells re...

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Detalles Bibliográficos
Autores principales: Yost, Kathryn E., Satpathy, Ansuman T., Wells, Daniel K., Qi, Yanyan, Wang, Chunlin, Kageyama, Robin, McNamara, Katherine, Granja, Jeffrey M., Sarin, Kavita Y., Brown, Ryanne A., Gupta, Rohit K., Curtis, Christina, Bucktrout, Samantha L., Davis, Mark M., Chang, Anne Lynn S., Chang, Howard Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689255/
https://www.ncbi.nlm.nih.gov/pubmed/31359002
http://dx.doi.org/10.1038/s41591-019-0522-3
Descripción
Sumario:Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of cancer patients(1). However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor infiltrating T cells (TILs) or on recruitment of novel T cells remains unclear(2–4). Here, we performed paired single-cell RNA (scRNA) 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 marked 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 TIL clones; rather, it was comprised of novel clonotypes not previously observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8(+) T cells and evident in BCC and SCC patients. 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.