KLF12 overcomes anti-PD-1 resistance by reducing galectin-1 in cancer cells
Yujia Zheng, Hao Zhang, Chu Xiao, Ziqin Deng, Tao Fan, Bo Zheng, Chunxiang Li, Jié He
Abstract
Backgrounds Immune checkpoint blockade has revolutionized cancer treatment and has improved the survival of a subset of patients with cancer. However, numerous patients do not benefit from immunotherapy, and treatment resistance is a major challenge. Krüppel-like factor 12 (KLF12) is a transcriptional inhibitor whose role in tumor immunity is unclear. Methods We demonstrated a relationship between KLF12 and CD8 + T cells in vivo and in vitro by flow cytometry. The role and underlying mechanism that KLF12 regulates CD8 + T cells were investigated using reverse transcription and quantitative PCR, western blot FACS, chromatin immunoprecipitation-PCR and Dual-Luciferase reporter assays, etc, and employing small interfering RNA (siRNA) and inhibitors. In vivo efficacy studies were conducted with multiple mouse tumor models, employing anti-programmed cell death protein 1 combined with KLF12 or galectin-1 (Gal-1) inhibitor. Results Here, we found that the expression of tumor KLF12 correlates with immunotherapy resistance. KLF12 suppresses CD8 + T cells infiltration and function in vitro and in vivo. Mechanistically, KLF12 inhibits the expression of Gal-1 by binding with its promoter, thereby improving the infiltration and function of CD8 + T cells, which plays a vital role in cancer immunotherapy. Conclusions This work identifies a novel pathway regulating CD8 + T-cell intratumoral infiltration, and targeting the KLF12/Gal-1 axis may serve as a novel therapeutic target for patients with immunotherapy resistance.