通过 IFN-γ 诱导的 I 型干扰素反应网络经 IRF7 增强 Th17 衍生 Th1 细胞的抗肿瘤疗效

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- -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- 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.