Macrophages in Colorectal Cancer

Colorectal cancer (CRC) is the most prevalent malignant digestive cancer characterized by its high prevalence and poor prognosis. Accumulating evidence has emphasized the vital role of the tumor microenvironment (TME) in the initiation and progression of CRC. In the TME, multiplex aspects of the relationship among tumor progression, immune response, and microbiome have been identified. Among these immune components, macrophages are particularly vast and play a distinctive role in cancer progression. Tumor-associated macrophages (TAMs), which are traditionally described as tumoricidal cells, have been identified in the original and metastatic lesions of CRC. while the macrophages in carcinogenesis are characterized by their protumoral ability in growth promotion, angiogenesis, metastasis, and immunosuppression.

Phenotypes of Macrophage in CRC

Macrophages are characterized distinctively as M1 and M2 macrophages, respectively due to their association with activation of T helper 1 and 2 cells. Under physiological conditions, M2 TAMs are predominated in the colonic lamina propria. As the development of adenomatous polyps, M1 TAMs begin to accumulate within the dysplastic polyps. Following the malignant conversion of the adenoma to CRC, TAMs gradually skew toward the M2 phenotype in the TME. Besides traditional M1/M2 macrophages, macrophages in the CRC can be classified by their function including activated macrophages, immunomodulatory macrophages, invasive macrophages, angiogenic macrophages, perivascular macrophages, and metastatic macrophages. Activated macrophages are related to the expression of TNF-α and IL-6 by macrophages in invasive CRC. Macrophages can also secrete IL-4 and IL-10, exhibiting an immunomodulatory role in tumor development. Moreover, invasive and angiogenic phenotypes of macrophages mediate invasion and angiogenesis. During metastasis, macrophages can polarize to perivascular phenotypes and subsequently metastasis-associated macrophages create a prometastatic niche for further progression. Accumulation of various protumoral macrophages in the TME is considered to impair immune surveillance and prevent tumoricidal inflammation, enhancing the growth and metastasis of CRC.

Fig.1 The main role of TAMs in the metastasis of CRC.^1,2

Exosomes from CRC Influence Macrophage Phenotypes

Exosomes are microvesicles in cell-to-cell communication. Exosomal proteins, miRNA and mRNA play vital roles in the development and metastasis of various cancers. Cancer-derived exosomes can mediate the polarization of TAM. It has been speculated that CRC cells can secrete chemoattractants to recruit monocytes to CRC that are further differentiated into M2 macrophage phenotypes, which can induce an immunosuppressive environment to facilitate CRC proliferation and metastasis.

Macrophage-derived Exosomes

Like most exosomes, macrophage-derived exosomes contain proteins and other factors that influence the TME and functions of other cell types. Exosomes from macrophages are believed to disturb the adhesion, morphology, and apoptosis of tumor cells, facilitating their migration, invasion, and metastasis in the microenvironment. Macrophage-derived exosomes can 1) mediate extracellular remodeling; 2) induce the expression of immune-phenotypic antigen; 3) regulate the epithelial-to-mesenchymal transformation of CRC.

Clinical Implications of TAMs in CRC

In contrast to most solid cancers, some studies indicate total TAM infiltration is found unable to predict the outcome, suggesting that different states of activation of macrophage subsets could be decisive in human CRC. Combining the TAM location and functional phenotype could represent a strategy to improve their prognostic value. In line with previous studies, CD163 is observed to be expressed by almost 40% of TAMs, in particular those that are located at the tumor invasive front. the use of CD80 as a marker of M1-polarized macrophages has shown that, in comparison to adjacent healthy mucosa, the majority of intra-tumoral macrophages downregulate CD80 and are, therefore, skewed towards an immunosuppressive phenotype. For stage II colon cancer, a high CD206/CD68 ratio is both an unfavorable prognostic biomarker and a positive predictive biomarker of response to postoperative adjuvant chemotherapy.

Therapies of Targeting TAMs in CRC

• Treatment with granulocyte macrophage- colony-stimulating factor (GM-CSF): GM-CSF (in combination with IFN-γ) can skew towards macrophages with an inflammatory profile. GM-CSF might represent a promising therapeutic agent in colorectal cancer.
• IFN-γ therapy: It was shown that IFN-γ reprograms cellular metabolism and regulates translation, which are key elements to induce inflammatory macrophage activation.
• Targeting pathogen recognition receptors: cytotoxicity can be stimulated with IFN-γ and/or ligands for pattern recognition receptors (PRR) such as LPS, Poly I:C, PAM3CSK4, muramyl peptides, or agonists.
• Increasing M1 TAMs by reprogramming macrophage polarization: colony-stimulating factor-1 (CSF-1) is one of the major differentiation and survival factors for macrophages. By inhibiting the CSF-1 receptor with either monoclonal antibodies (mAbs) or small molecule inhibitors macrophages become more prone to factors such as GM-CSF and IFN. These signals induce repolarization into macrophages with anti-tumor properties.
• mAb Therapy: Anti-tumour mAbs greatly enhance the ability of macrophages to phagocytose tumor cells. Several studies support that macrophages are the primary effector cells during mAb therapies currently used in the clinic.

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References

1. Hou, Siyu, et al. "Tumor-associated macrophages in colorectal cancer metastasis: molecular insights and translational perspectives." Journal of Translational Medicine 22.1 (2024): 62.
2. Under Open Access license CC BY 4.0, without modification.