RECQL4 Remodels the Tumor Immune Microenvironment via the cGAS-STING Pathway in Hepatocellular Carcinoma

Abstract

<h3>Purpose/Objective(s)</h3> RECQL4 was considered a susceptible target for cancer therapy by playing diverse roles in the maintenance of genomic stability. Understanding more about the molecular characteristics of RECQL4 enables the better selection of HCC patients who would derive benefit from radiation therapy (RT) combined with immune checkpoint immunotherapies (ICIs). <h3>Materials/Methods</h3> We collected RNA sequencing data of 1175 HCC and 767 adjacent non-tumor tissues from 5 cohorts, followed by comprehensive evaluation of the expression patterns and multi-omics characteristics of RECQL4. Then, the expression of RECQL4 was systematically associated with HCC genomic instability and tumor microenvironment (TME) with multi-omics data and multicolor immunofluorescence staining. cGAS^−/− and STING^−/- mice were used to determine the relation of RECQL4 and cGAS-STING signaling pathway in HCC in vivo. Finally, clinical and pathologic data were collected retrospectively on HCC patients at the Zhongshan Hospital of Fudan University and associations with survival were determined. <h3>Results</h3> We found that RECQL4 was specifically overexpressed in HCC and significantly associated with a poor prognosis. The CNV results showed RECQL4 mutations was mainly caused by 8q24 and the expression was positive correlation with CNV burden. Moreover, RECQL4 expression was significantly and negatively correlated with the infiltrating levels of dendritic cells (DCs) and CD8 + T cells, which means high RECQL4 designed a non-inflamed TME. Low RECQL4 induces DCs maturation and antigen presentation by triggering the cGAS-STING pathway, and further activates CD8 + T cell-mediated the adaptive immunity. The result was further confirmed in RT combined with ICIs of HCC, which suggests that low RECQL4 bridges the DNA damaging capacity of RT with the CD8+ cytotoxic T cell-mediated destruction of cancer through innate immune signaling cGAS–STING to make the combined therapy better efficacy. Retrospective analysis also showed that HCC patients with low RECQL4 expression were more sensitive to RT with ICIs. <h3>Conclusion</h3> RECQL4 mediates a non-inflamed TME by regulating the cGAS-STING pathway on immune cells in HCC. HCC patients with low RECQL4 could derive response and benefit from several treatment options. RECQL4 serves as a new target for HCC radiotherapy combined with immunotherapy.