Antagonistic roles of cGAS/STING signaling in colorectal cancer chemotherapy

作者：Beiyuan Liang, Xuanxuan Xing, Hayden Storts, Zhen Ye, Hazel Claybon, Ryan Austin, Rachel Ding, Bei Liu, Haitao Wen, Wayne Miles, Richard Fishel, Jing J. Wang · 发表于：Frontiers in Oncology · 年份：2024 · DOI：10.3389/fonc.2024.1441935 · 被引用次数：16 · 研究领域：interferon and immune responses、Immune Cell Function and Interaction、Cancer Immunotherapy and Biomarkers

FOLFOX, composed of 5-FU, oxaliplatin and leucovorin, is a first line chemotherapy regimen for colorectal cancer (CRC) treatment. In this study, we show that 5-FU and oxaliplatin induce DNA damage and activate cGAS/STING signaling leading to enhanced expression of interferon (IFN) β, IFN-stimulated genes and inflammatory cytokines in mouse and human colon cancer cells as well as increased intratumoral CD8 + T cells in mice. Crucially, 5-FU and oxaliplatin increase PD-L1 expression at the mRNA and protein levels, which has been shown to inhibit CD8 + T cell function. Depletion of cGAS, STING, IRF3, or IFNα/β receptor 1 (IFNAR1) abolishes this increase, indicating that 5-FU/oxaliplatin mediated upregulation of PD-L1 expression is dependent on tumor cell intrinsic cGAS/STING signaling. These results imply opposing roles for FOLFOX during cancer treatment. On one hand, 5-FU and oxaliplatin activate the innate immune response to facilitate anti-tumor immunity, and conversely upregulate PD-L1 expression to evade immune surveillance. Analysis of TCGA colon cancer dataset shows a positive correlation between expression of PD-L1 and components of the cGAS/STING pathway, supporting a role for cGAS/STING signaling in upregulating PD-L1 expression in colon cancer patients. Tumor studies in syngeneic immune competent mice demonstrate that the combination of 5-FU/oxaliplatin and anti-PD-1 significantly reduced tumor growth of colon cancer cells compared to 5-FU/oxaliplatin treatment alone....