CELL INTELLIGENCE · 肿瘤细胞治疗研究

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has demonstrated clinical success in solid tumors. We analyze 47 TIL infusion products and 62 pretreatment tumor microenvironments (TMEs) from a randomized phase 2 clinical study of concurrent chemoradiotherapy plus TIL-ACT (NCT02421640). Using single-cell and bulk RNA sequencing along with flow cytometry, we identify 14 CD3 + T cell clusters within 26 TIL infusion products: 11 CD3 + CD8 + TILs, 2 CD3 + CD4 + TILs, and 1 CD3 + CD8 - CD4 - double-negative (DN) TIL. (DN) TILs, significantly associated with poor TIL-ACT outcomes, exhibit an activated regulatory T cell-like phenotype and include two CD56 + and four CD56 - subsets. Among them, CD56 - KZF2 + (DN) TILs are predominantly suppressive. (DN) TILs inhibit CD8 + TIL expansion via Fas-FasL, transforming growth factor (TGF- ), and interleukin (IL)-10 signaling. Distinct CD8 + T subsets differentially impact on TIL-ACT outcomes, while 9 baseline TME gene signatures and 14 intracellular T cell genes hold prognostic value. Our findings identify predictive TIL subsets and biomarkers for TIL-ACT outcomes.