CD40 Pathway and IL-2 Expression Mediate the Differential Outcome of Colorectal Cancer Patients with Different <i>CSF1R</i> c.1085 Genotypes

Abstract

Background: Colony-stimulating factor 1 receptor (CSF-1R) acts as the receptor for colony stimulating factor 1, a cytokine which controls the production, differentiation , and function of macrophages. Prior studies showed cancer patients harboring germline CSF1R c.1085A>G genetic variant had a better survival. Here, we studied the immune mechanism underlying the different outcomes. Materials and Methods The clinical outcome for CSF1R c.1085 genotype A_A or A_G was analyzed in a colorectal cancer (CRC) cohort. Primary CRC tumor samples were used to study the tumor immune microenvironment by a targeted gene expression assay containing 395 immune-related genes. Immunofluorescent and immunohistochemical staining were used to validate the findings of gene expression. Findings: CRC patients with CSF1R c.1085 genotype A_G had a better disease-free survival and overall survival than those with CSF1R genotype A_A. Compared to the group of patients without CSF1R variant, higher CD40LG expression, a surface marker of T cells, was found in the tumor tissues of patients with CSF1R c.1085 variant. In parallel with the higher CD40LG gene expression, immunofluorescent staining also showed more CD3+CD40L+ T cell infiltrates in tumors with CSF1R c.1085 genotype A_G. Moreover, higher IL-2 expression, known to be regulated by CD40 pathway, was also observed in tumors with CSF1R c.1085 genotype A_G than those with genotype A_A. Interpretation: Higher IL-2 expression generated by the interaction of CD40 ligand and CD40 between T cells and macrophages with CSF1R c.1085 genotype A_G is the potential mechanism explaining why CRC patients with this germline variant had a better clinical outcome. Funding Statement: National Cheng Kung University Hospital and Chi-Mei hospital (CMNCKU10504) and Ministry of Health and Welfare (MOHW108-TDU-B-211-124018 & MOHW108-TDU-B-211-133003). Declaration of Interests: The authors declare no conflicts of interests with relevance to this study. Ethics Approval Statement: These 2 studies were approved by the institutional review board (A-ER-103-395 & A-ER-1040153) of National Cheng Kung University Hospital (NCKUH) and conducted in accordance with the Declaration of Helsinki. Written informed consents were provided by all patients.