1234 Immunotherapy induces clonal expansion of cytotoxic tumor-specific TILs in a model of melanoma

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 recurrence death. Tumor infiltrating lymphocytes (TILs) are heterogeneous population that play critical roles in response to aCTLA4/aPD1 remain incompletely characterized. Specifically, changes TIL composition induced by immunotherapy precise identity cells mediate antitumor cytotoxicity unclear. Here, we use BrafV600E driven model characterize single-cell transcriptional TCR profiles tumor-specific TILs during CTLA-4/PD-1 blockade vivo. Using paired scRNA-Seq, TCR-seq MHC-tetramer CITE-Seq, analyze ecosystem therapy exhaustion (control). We uncover dominant clonotype emerges occupy 35% entire repertoire. The program this CD8+ has cytotoxic NK cell-like properties, expression killer cell lectin receptor family members, cathepsin W, interferon transmembrane proteins (IFITM, p=1.47E-08), no markers. In contrast, exhausted compartment contained several clonal populations with features including Pdcd1, Lag3, Havcr2 Tigit (p<0.005). integrate our findings human find signature present TME associated longer overall survival (p<0.0001). Our results demonstrate how CTLA4/PD-1 alters at single level describes which likely be involved cytotoxicity. anticipate will improve understanding subpopulations their role immune melanoma.