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

Wu-Chou Su,Peng-Chan Lin,Meng-Ru Shen,Yu-Min Yeh

doi:10.3390/ijms222212565

Abstract

Colony-stimulating factor 1 receptor (CSF-1R) acts as the receptor for colony stimulating factor 1, a cytokine that controls the production, differentiation, and function of macrophages. Prior studies showed cancer patients harboring germline CSF1R c.1085A>G genetic variant had better survival. Here, primary tumor samples from a stage III colorectal cancer (CRC) cohort were analyzed by a targeted gene expression assay containing 395 immune-related genes to study the immune mechanism underlying the different outcomes. CRC patients with CSF1R c.1085 genotype A_G had a better disease-free 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 genotype A_A. Higher IL-2 expression generated by the interaction of CD40 ligand and CD40 between T cells and macrophages with CSF1R c.1085A>G variant is the potential mechanism explaining the different outcomes.

Highlights

IntroductionThe immunotherapy targeting cytotoxic T lymphocyte-associated protein 4 (CTLA4)
The immunotherapy targeting cytotoxic T lymphocyte-associated protein 4 (CTLA4)and programmed cell death 1 (PD-1) has recently been demonstrated to be an effective approach to activate immune response and treat a wide range of cancers [1]
A total of 109 stage III or high-risk stage II colorectal cancer (CRC) patients enrolled in the chemotherapy-induced peripheral neuropathy (CIPN) study were used to study the potential mechanism mediating the different clinical outcome between patients with CSF1R c.1085 genotype A_A and A_G (Figure S1)

Summary

Introduction

The immunotherapy targeting cytotoxic T lymphocyte-associated protein 4 (CTLA4). Programmed cell death 1 (PD-1) has recently been demonstrated to be an effective approach to activate immune response and treat a wide range of cancers [1]. The most dominant and import immune infiltrates in the tumor microenvironment are macrophages, which are often termed as tumor-associated macrophages [3]. These macrophages exhibit pro-tumorigenic effects by suppressing anti-tumor immune response of effector cells, including T cells and NK cells, and promoting tumor proliferation, survival, and metastasis. Targeting tumor-associated macrophages, especially the tumor-promoting M2-like macrophages, has become a promising therapeutic strategy to improve the efficacy of current immunotherapy in recent years

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