Runx-mediated regulation of CCL5 via antagonizing two enhancers influences immune cell function and anti-tumor immunity

Abstract

CCL5 is a unique chemokine with distinct stage and cell-type specificities for regulating inflammation, but how these specificities are achieved and how CCL5 modulates immune responses is not well understood. Here we identify two stage-specific enhancers: the proximal enhancer mediates the constitutive CCL5 expression during the steady state, while the distal enhancer located 1.35 Mb from the promoter induces CCL5 expression in activated cells. Both enhancers are antagonized by RUNX/CBFβ complexes, and SATB1 further mediates the long-distance interaction of the distal enhancer with the promoter. Deletion of the proximal enhancer decreases CCL5 expression and augments the cytotoxic activity of tissueresident T and NK cells, which coincides with reduced melanoma metastasis in mouse models. By contrast, increased CCL5 expression resulting from RUNX3 mutation is associated with more tumor metastasis in the lung. Collectively, our results suggest that RUNX3mediated CCL5 repression is critical for modulating anti-tumor immunity.

Exploration and validation of related hub gene expression during SARS-CoV-2 infection of human bronchial organoids

“…In addition, CCL5 can directly activate M1 (pro-inflammatory) polarization and prevent M2 (anti-inflammatory) polarization [ 30 ]. The lack of homeostatic CCL5 expression will largely influence the activated state of lung TRM (tissue-resident memory) T cell and natural killer cell components [ 31 ].…”

The CCL5/CCR5 Axis in Cancer Progression

“…This review focuses on the CCL5/CCR5 axis, which is the main actor in tumor progression [19,20]. However, CCL5 is a double-edged sword in cancer, because it also promotes antitumor immunity by recruiting anti-tumor T cells and dendritic cells to the TME, and therefore enhances the immunotherapy response in different tumor types [21][22][23][24][25].…”

Prognostic Value of a Ten-Gene Signature in HNSCC Patients Based on Tumor-Associated Macrophages Expression Profiling

“…Inflammatory factors produced by endothelial cells promote PTGDS expression and release PGD2, which inhibited malignant biological behavior of vascular permeability, angiogenesis, EMT, and tumor apoptosis (30). CCL5, a specific chemokine released by macrophages, regulates inflammation, of which its role in tumor progression is controversial (31). Knockdown of glycogen branching enzyme (GBE1) downstream of HIF1 in lung adenocarcinoma led to an increase in CCL5 expression and recruited more cytotoxic CD8 + T lymphocytes to contribute to tumor regression (32).…”