Augmenting antitumor efficacy of Th17-derived Th1 cells through IFN-γ-induced type I interferon response network via IRF7.

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 Th1 cells within tumors. Subsequent trajectory analysis found that these Th1 cells are initially primed under Th17 conditions and then converted into IFN-γ-producing cells. Following the in vivo differentiation trajectory of Th1 cells, we successfully established in vitro Th1 cell culture. Transcriptomic profiling has unveiled a substantial resemblance between in vitro-generated Th1 cells and their tumor-infiltrating counterparts. Th1 cells exhibit more potent antitumor responses than Th1 or Th17 cells. Additionally, Th1chimeric antigen receptor T (CAR-T) cells eradicate solid tumors more efficiently. Importantly, Th1 cells display an early exhaustion phenotype while retaining stemness. Mechanistically, Th1 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 Th1 cells. Taken together, our findings position Th1 cells as a great candidate for improving targeted immunotherapies in solid malignancies.