Augmenting antitumor efficacy of Th17-derived Th1 cells through IFN-γ-induced type I interferon response network via...

The importance of CD4⁺ T cells in cancer immunotherapy has gained increasing recognition. Particularly, a specific subset of CD4⁺ T cells coexpressing the T helper type 1 (Th1) and Th17 markers has demonstrated remarkable antitumor potential. However, the underlying mechanisms governing the differentiation of these cells and their subsequent antitumor responses remain incompletely understood. Single-cell RNA sequencing (scRNA-seq) data reanalysis demonstrated the presence of Th₁₇1 cells within tumors. Subsequent trajectory analysis found that these Th₁₇1 cells are initially primed under Th17 conditions and then converted into IFN-γ-producing cells. Following the in vivo differentiation trajectory of Th₁₇1 cells, we successfully established in vitro Th₁₇1 cell culture. Transcriptomic profiling has unveiled a substantial resemblance between in vitro-generated Th₁₇1 cells and their tumor-infiltrating counterparts. Th₁₇1 cells exhibit more potent antitumor responses than Th1 or Th17 cells. Additionally, Th₁₇1chimeric antigen receptor T (CAR-T) cells eradicate solid tumors more efficiently. Importantly, Th₁₇1 cells display an early exhaustion phenotype while retaining stemness. Mechanistically, Th₁₇1 cells migrate faster and accumulate more in tumors in an extracellular matrix protein 1 (ECM1)-dependent manner. Furthermore, we show that IFN-γ up-regulated IRF7 to promote the type I interferon response network and ECM1 expression but decreased the exhaustion status in Th₁₇1 cells. Taken together, our findings position Th₁₇1 cells as a great candidate for improving targeted immunotherapies in solid malignancies.