CXCR6+ Tumor-Associated Macrophages Identify Immunosuppressive Colon Cancer Patients with Poor Prognosis but Favorable Response to Adjuvant Chemotherapy

SIMPLE SUMMARY: In this study, we first reported the infiltration and prognostic value of CXCR6+TAMs in all stages of colon cancer patients and assessed predictive ability as a biomarker for different duration adjuvant chemotherapy regimens in the primary cohort and validation cohort Patients with high CXCR6+ TAM infiltration tended to have worse overall survival. A 6-month chemotherapy regimen for high-risk stage II and stage III patients after curative operation benefited those with high CXCR6+ TAM density the most. Furthermore, we found there was a negative relationship between CXCR6+TAMs and activated CD8+ T cells. Cytokines from peripheral blood reflected the immunosuppressive state in patients with high accumulations of CXCR6+TAMs This indicates that CXCR6+TAMs may be involved in the formation of an immunosuppressive environment. ABSTRACT: We explored the infiltration and prognostic value of CXCR6+TAMs in all stages of colon cancer (CC) patients and assessed predictive ability as a biomarker for different ACT regimens among high-risk stage II and stage III patients in both primary and validation cohorts. Two independent cohorts of 360 and 126 consecutive colon cancer patients were enrolled from two medical centers of Zhongshan Hospital. Immunofluorescence and immunohistochemistry were performed to detect the density of CXCR6+TAMs and activated CD8+ T cells. The infiltration of CXCR6+TAMs was higher in tumor tissues and increased with advanced tumor stage. A high density of CXCR6+TAMs predicted worse overall survival (OS) in all CC patients (HR = 2.49, 95% CI = (1.68, 3.70), p < 0.001), and was an independent risk factor verified by Cox regression analysis (HR = 1.68, 95% CI = (1.09, 2.59), p = 0.019). For high-risk stage II and stage III patients with a high density of CXCR6+TAMs, better disease-free survival (DFS) (HR = 0.32, 95% CI = (0.11, 0.89), p = 0.003), and OS (HR = 0.28, 95% CI = (0.07, 1.11), p = 0.014) were observed in the 6-month treatment group. There was a negative relationship between the density of CXCR6+TAMs and CD8+ T cells (R = −0.51, p < 0.001) as well as activated CD8+ T cells (R = −0.54, p < 0.001). Higher levels of IL-6 and lower levels of IL-2R and TNF-α were expressed in high-CXCR6+ TAM-density patients, which indicates that CXCR6+TAMs contribute to an immunosuppressive microenvironment. CXCR6+TAMs predicted prognosis and response to different durations of ACT in CC patients. CXCR6+TAMs were associated with an immunosuppressive microenvironment and suppressed the activation of CD8+ T cells.