Tumor-associated Macrophages as Prognostic and Predictive Biomarkers for Postoperative Adjuvant Chemotherapy in Patients with Stage II Colon Cancer

Abstract

Purpose: For stage II colon cancer, the efficacy of postoperative adjuvant chemotherapy remains controversial. It is well known that tumor-associated macrophages (TAMs) are important in tumor progression. In this study, TAMs were investigated as prognostic and predictive biomarkers for the efficacy of adjuvant chemotherapy for stage II colon cancer after radical resection. Experimental Design: This study enrolled two independent cohorts of consecutive patients from one medical center with pathologic stage II colon cancer after radical resections. Macrophages were detected using IHC staining of CD68 and CD206. Infiltration densities of CD68 þ TAMs, CD206 þ TAMs, and ratio of CD206 þ TAMs/CD68 þ TAMs (CD206/CD68 ratio) were calculated as prognostic and predictive biomarkers. Results: The primary and validation cohorts consisted of 521 and 314 patients, respectively. In both cohorts, high CD206/CD68 ratio was significantly associated with poor disease-free survival (DFS) and overall survival (OS). As an independent risk factor, CD206/CD68 ratio also had significantly better prognostic efficacy than CD68 þ TAM density, CD206 þ TAM density, and traditional clinicopathologic highrisk factors. Moreover, adjuvant chemotherapy significantly improved DFS and OS for patients with high CD206/CD68 ratio but not for those with low CD206/CD68 ratio. The interaction analyses were also significant for DFS. In subgroup analysis, CD206/CD68 ratio was still a significant predictor for adjuvant chemotherapy for patients in traditional high-risk group of recurrence (significant interaction for DFS). Conclusions: For stage II colon cancer, CD206/CD68 ratio is a better prognostic and predictive biomarker for postoperative adjuvant chemotherapy. Together with clinicopathologic high-risk factors, it will aid in precision treatment.

Macrophage Colony-stimulating Factor Mediates the Recruitment of Macrophages in Triple negative Breast Cancer

“…Classified as part of the mononuclear phagocytic system (MPS), macrophages are a group of terminally differentiated cells that play a critical role in tissue homeostasis, inflammation, and protection against pathogenic infections. As reported previously, the presence of TAM was associated with poor clinical outcome in patients with glioma, cholangiocarcinoma, ovarian, breast cancer, and Hodgkin's lymphoma [26][27]. TAMs were involved in an indirect mechanism of promoting tumorigenesis, tumor metastasis and tumor neovascularization along with the tumor-derived angiogenic factors [28].…”

The local inflammatory response in colorectal cancer – Type, location or density? A systematic review and meta-analysis

“…Alexander, et al Cancer Treatment Reviews 83 (2020) 101949 in immune resistance [170]. CD68 is a generic macrophage marker, whereas CD163 and CD206 are believed to be markers more specific to M2 tumour associated macrophages that have been associated with a worse outcome [171]. There were twenty-two studies overall in colon or colorectal cancer although one study had an overlapping population [172], leaving twenty-one independent studies comprising 4879 patients [60,83,85,87,89,91,96,111,122,123,168,171,[173][174][175][176][177][178][179][180][181].…”

“…CD68 is a generic macrophage marker, whereas CD163 and CD206 are believed to be markers more specific to M2 tumour associated macrophages that have been associated with a worse outcome [171]. There were twenty-two studies overall in colon or colorectal cancer although one study had an overlapping population [172], leaving twenty-one independent studies comprising 4879 patients [60,83,85,87,89,91,96,111,122,123,168,171,[173][174][175][176][177][178][179][180][181]. Of these, eleven studies (2038 patients) found that higher infiltration of macrophages were associated with a better prognosis [60,83,87,96,122,[175][176][177][178]180,181], compared with five studies (1965 patients) finding a worse prognosis [85,168,171,173,179].…”

“…In colon cancer, two studies (1070 patients) assessed macrophage markers and survival. One study of 835 patients assessed CD68 and CD206 [171]. CD68 assessment in the intratumoural stromal compartment was not associated with survival, whereas CD206 was associated with worse survival [171].…”

“…One study of 835 patients assessed CD68 and CD206 [171]. CD68 assessment in the intratumoural stromal compartment was not associated with survival, whereas CD206 was associated with worse survival [171]. The other paper assessed CD163 in the intratumoural stromal compartment, which was associated with worse survival [173].…”