TNFRSF11B Remodel Immune Response in Colon Cancer Microenvironment: A Multi-Center Study

Background: Colorectal cancer is the lethal cancer in the world, due to the low tumor mutation burden and low proportion of tumor-infiltrating lymphocytes in the microenvironment of most patients, innovative immunotherapeutic approaches need to be identified. Methods: Using TCGA-COAD dataset (n = 514), we identified TNFRSF11B as a prognostic factor of colon cancer. Immunohistochemistry (IHC) dataset (n = 86), 290 single colorectal cancer cells (GSE81861) and 31 paired colon cancer transcriptional dataset were further applied to validate the function of TNFRSF11B, which was confirmed via fluorescence-activated cell sorting (FACS) analysis.   Results: A risk scores system consisting of eight IRGs was constructed to predict the prognosis of colon cancer patients. Only TNFRSF11B correlated with TNM-stage, lymph node metastasis and prognosis. In our IHC dataset, High TNFRSF11B expression had a later TNM-stage, higher frequency of lymph node and lymphovascular invasion. Six genes (KRT18, ARPC5L, ACTG1, ARPC2, EZR, YWHAZ) related to pathogenic E. coli. infection were simultaneously increased with TNFRSF11B overexpression via GESA analysis. Finally, only activated memory CD4+ T cells (p =0.017) were significantly decreased in high TNFRSF11B expression group, which was supported by our FACS findings that TNFRSF11B downregulate the immune activity of central memory CD4 + T cells and effector memory CD4+ T cells (all p <0.001). Conclusion: TNFRSF11B, acts as a prognostic factor for colon cancer patient, could affect colon cancer immune response. TNFRSF11B was closely related with lymph node invasion and pathogenic E. coli. infection, which might negatively affect memory activated CD4+ T cell infiltration in colon cancer. Funding: This work was supported Joint Funds for the innovation of science and Technology, Fujian province (Grant number: 2018Y9203 to Jun-rong Zhang, 2018Y92042 to Xian-qiang Chen); Startup Fund for scientific research, Fujian Medical University (Grant number: 2019QH1016 to Ping Hou); Education Department of Fujian Province Young and middle-aged teacher education research project (Grant number: JAT190180 to Ping Hou, JT180181 to Jun-rong Zhang). Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: The validation of TNFRSF11B in paraffin-embedded colorectal cancer tissues were supported by general surgery of Fujian Medical University Union Hospital from January 2013 to December 2017. The study protocol was approved by the Institutional Review Board of Fujian Medical University Union Hospital, and all patients provided written informed consent.