Hypoxia and Macrophages Act in Concert Towards a Beneficial Outcome in Colon Cancer

Abstract

In colon cancer, the prognostic value of macrophages is controversial, and it is still unknown how hypoxia modulates macrophage–cancer cell crosstalk. To unravel this, co-cultures of human primary macrophages and colon cancer cells were performed at 20% and 1% O2, followed by characterization of both cellular components. Different colon cancer patient cohorts were analyzed for hypoxia and immune markers, and their association with patient overall survival was established. A positive correlation between HIF1A and CD68 in colon cancer patients was identified but, unexpectedly, in cases with higher macrophage infiltration, HIF1A expression was associated with a better prognosis, in contrast to breast, gastric, and lung cancers. Under hypoxia, co-cultures’ secretome indicated a shift towards a pro-inflammatory phenotype. These alterations occurred along with increased macrophage phagocytic activity and decreased SIRPα expression. Cancer cells were more invasive and exhibited higher CD47 expression. We hypothesize that the better prognosis associated with HIF1AHighCD68High tumors could occur due to macrophagic pro-inflammatory pressure. Indeed, we found that tumors HIF1AHighCD68High expressed increased levels of CD8A, which is positively correlated with HIF1A. In conclusion, we show that in colon cancer, hypoxia drives macrophages into a pro-inflammatory phenotype, concomitant with increased infiltration of anti-tumor immune cells, favoring better disease outcome.

Trophoblast-derived Lactic Acid Orchestrates Decidual Macrophage Differentiation via SRC/LDHA Signaling in Early Pregnancy

“…There are few in-vitro studies in tumors using hypoxic condition to investigate the effects of LA or tumor-conditioned media on the macrophage polarization. In a recent study of colon cancer by Martins et al [41], they co-cultured human primary macrophages with colon cancer cells under 20% (normoxia) and 1% (hypoxia) O2, and found that hypoxia drived macrophages into a M1-phenotype. Their results support our findings that normoxia and hypoxia have different effects on the polarization of macrophages.…”

The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies

“…However, hypoxia may have beneficial effects on cancer therapy via SIRPα-CD47 axis. Colon cancer has a better prognosis than other cancer types because it has higher levels of macrophage infiltration and HIF-1α expression [ 104 ]. Hypoxia can decrease SIRPα expression in macrophages while simultaneously increasing CD47 expression in colon cancer cells.…”

“…Hypoxia can decrease SIRPα expression in macrophages while simultaneously increasing CD47 expression in colon cancer cells. The heightened signal of "don't eat me" is countered by the reduced SIRP expression level, increasing the phagocytic capacity of macrophages [ 104 ]. Therefore, HIF-1α does have the ability to enhance phagocytosis of macrophages, which may be dependent on cancer types [ 158 ].…”

Natural Killer Cell-Derived Extracellular Vesicles as a Promising Immunotherapeutic Strategy for Cancer: A Systematic Review

“…The development of cell-based immunotherapy can be achieved by establishing cell lines that express tumor selectivity and cytotoxic functions. Several prospective candidates that have been rigorously studied are natural killer (NK) cells, dendritic cells (DC), macrophages and T-lymphocytes [ 13 , 14 , 15 , 16 ]. These cells play critical roles in alerting the immune system (e.g., chemotaxis), arming other immune cells (e.g., antibody-dependent and cytokine-dependent activation) and exerting their cytotoxic effect against the cancer cells (e.g., receptor-mediated cell apoptosis).…”