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 Th ₁₇ 1 cells within tumors. Subsequent trajectory analysis found that these Th ₁₇ 1 cells are initially primed under Th17 conditions and then converted into IFN-γ-producing cells. Following the in vivo differentiation trajectory of Th ₁₇ 1 cells, we successfully established in vitro Th ₁₇ 1 cell culture. Transcriptomic profiling has unveiled a substantial resemblance between in vitro-generated Th ₁₇ 1 cells and their tumor-infiltrating counterparts. Th ₁₇ 1 cells exhibit more potent antitumor responses than Th1 or Th17 cells. Additionally, Th ₁₇ 1chimeric antigen receptor T (CAR-T) cells eradicate solid tumors more efficiently. Importantly, Th ₁₇ 1 cells display an early exhaustion phenotype while retaining stemness. Mechanistically, Th ₁₇ 1 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 Th ₁₇ 1 cells. Taken together, our findings position Th ₁₇ 1 cells as a great candidate for improving targeted immunotherapies in solid malignancies.
Competing Interests: Competing interests statement:The authors declare no competing interest.