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- W4366184498 abstract "Melanoma is the deadliest form of skin cancer causing over 50,000 deaths annually worldwide. Immune checkpoint inhibitors (aCTLA4/aPD1) have improved melanoma survival, but many patients do not respond and face a high risk of recurrence and death. Tumor infiltrating lymphocytes (TILs) are a heterogeneous population that play critical roles in response to aCTLA4/aPD1 but remain incompletely characterized. Specifically, the changes in TIL composition induced by immunotherapy and the precise identity of cells that mediate antitumor cytotoxicity are unclear. Here, we use a BrafV600E driven model of melanoma to characterize the single-cell transcriptional and TCR profiles of tumor-specific TILs during response to CTLA-4/PD-1 blockade in vivo. Using paired scRNA-Seq, TCR-seq and MHC-tetramer CITE-Seq, we analyze the TIL ecosystem during therapy (aCTLA4/aPD1) and exhaustion (control). We uncover a dominant clonotype of tumor-specific TILs that emerges in response to immunotherapy to occupy 35% of the entire TIL TCR repertoire. The transcriptional program of this CD8+ population has cytotoxic and NK cell-like properties, expression of killer cell lectin receptor family members, cathepsin W, and interferon induced transmembrane proteins (IFITM, p=1.47E-08), but no exhaustion markers. In contrast, the exhausted TIL compartment contained several clonal CD8+ populations with features of exhaustion including Pdcd1, Lag3, Havcr2 and Tigit expression (p<0.005). We integrate our findings with human melanoma and find that the cytotoxic signature is present in the TME and associated with longer overall survival (p<0.0001). Our results demonstrate how CTLA4/PD-1 blockade alters the TIL composition at a single cell level and describes a clonal cytotoxic TIL population which is likely to be involved in antitumor cytotoxicity. We anticipate that our findings will improve the understanding of immunotherapy induced changes of TIL subpopulations and their role in the immune response to melanoma." @default.
- W4366184498 created "2023-04-19" @default.
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- W4366184498 date "2023-05-01" @default.
- W4366184498 modified "2023-09-28" @default.
- W4366184498 title "1234 Immunotherapy induces clonal expansion of cytotoxic tumor-specific TILs in a model of melanoma" @default.
- W4366184498 doi "https://doi.org/10.1016/j.jid.2023.03.1248" @default.
- W4366184498 hasPublicationYear "2023" @default.
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