Journal for ImmunoTherapy of Cancer (Aug 2023)

KLF12 overcomes anti-PD-1 resistance by reducing galectin-1 in cancer cells

  • Hao Zhang,
  • Jie He,
  • Chunxiang Li,
  • Tao Fan,
  • Bo Zheng,
  • Chu Xiao,
  • Yujia Zheng,
  • Ziqin Deng

DOI
https://doi.org/10.1136/jitc-2023-007286
Journal volume & issue
Vol. 11, no. 8

Abstract

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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.