Abstract 5132: The immunomodulatory role of paracrine signaling factor VSIG4 in peritoneal cancers

Abstract Introduction: Colorectal cancer (CRC) is one of the most common cancers worldwide, often presenting with regional spread to the peritoneum. Peritoneal carcinomatosis (PC) has a significantly poorer prognosis compared to metastasis to the other regions of the body. Immunotherapy makes use of the memory and specificity of the adaptive immune system to achieve long lasting effective anti-tumor response. Tumor associated macrophages (TAMs) in the tumor microenvironment have been implicated in tumorigenesis by creating an anti-inflammatory environment suitable for the growth of cancer cells. Thus, our group sought to identify factors associated with immunomodulation in colorectal PC. Methods: We interrogated publicly available colorectal cancer single cell database (n=5) to identify putative immune markers associated with macrophage activation in cancers. Validation was performed using V-set and immunoglobulin containing domain 4 (VSIG4) immunohistochemistry (IHC) staining on tumor microarrays (TMAs) of colorectal primary tumors (n=210). VSIG4 protein expression was assessed in cell-free ascites (n=39) derived from PC. Results: Using publicly available single cell database, we shortlisted the top 100 genes from the expression data of CD136-positive TAMs cluster. Among these macrophage-associated genes, two putative markers, VSIG4 and NR1H3, were involved in the regulation of macrophage activation. NR1H3, also known as liver X receptor-alpha (LXR-α), is particularly associated with cholesterol metabolism and thus was excluded from our exploration of TAMs activity. Interestingly, our target of choice, VSIG4, is a membrane protein expressed by M2 macrophages, which is associated with the activation of anti-inflammatory macrophage subtype and the downregulation of pro-inflammatory macrophages. IHC staining of CRC TMA demonstrated that low VSIG4 expression in stroma of primary CRC is associated with poor prognosis (p=0.018). Moreover, enzyme-linked immunosorbent assay (ELISA) of the ascites from colorectal PC patients showed varying amounts of VSIG4, suggesting a possible biological role of VSIG4 amongst patients with upregulated VSIG4 levels in ascites. Taken together, our studies suggest that VSIG4 plays a possible immunomodulatory role in colorectal PC and warrants further studies to assess its potential role as a therapeutic target in PC. Conclusion: In view of its potential as a target for immunotherapy, further studies should be conducted to understand the role of VSIG4 in the progression of colorectal PC. Citation Format: Yik Yan Chong, Sasinthiran Thiagarajan, Qiu Xuan Tan, Hui Jun Lim, Joey Wee-Shan Tan, Josephine Hendrikson, Gillian Ng, Ying Liu, Clara Yieh Lin Chong, Chin Jin Seo, Jolene Si Min Wong, Claramae Shulyn Chia, Nicholas Brian Shannon, Chin-Ann Johnny Ong. The immunomodulatory role of paracrine signaling factor VSIG4 in peritoneal cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5132.