淋巴毒素驱动的杀伤性 CD8⁺ TIL 清除癌细胞

Tumor-infiltrating lymphocyte (TIL) therapy is FDA-approved for patients with treatment-resistant advanced melanoma, but the TIL subpopulations critical for tumor eradication remains incompletely understood. Using patient-derived TIL-melanoma co-cultures, we identified and characterized a novel subset of CD8 + TIL, capable of class I HLA-independent cancer cell lysis. The lymphotoxin receptor (LT R) and interferon (IFN) sensing pathways were nominated as key determinants of TIL-mediated cancer cell killing from a whole-genome, loss-of-function CRISPR screen.

Validation studies confirmed that dual LT R and IFN sensing is necessary and sufficient for cancer cell lysis, and that expanded CD8 + TIL express high lymphotoxin ( LTB ) and upregulate lymphotoxin ( LTA ) upon coculture with cancer cells. Leveraging paired scRNA-seq and scTCR-seq data, we confirmed that enrichment of LTB + CD8 + T cells is associated with clinical response to TIL, and that LTB + CD8 + TIL are expanded from putative neoantigen-reactive, LTB lo CD8 + T cells in resected tumors.