Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice

Abstract

Tumor-associated macrophages (TAMs) as immune cells within the tumor microenvironment have gained much interests as basic science regarding their roles in tumor progression unfolds. Better understanding of their polarization into pro-tumoral phenotype to promote tumor growth, tumor angiogenesis, immune evasion, and tumor metastasis has prompted various studies to investigate their clinical significance as a biomarker of predictive and prognostic value across different cancer types. Yet, the methodologies to investigate the polarization phenomena in solid tumor tissue vary. Nonetheless, quantifying the ratio of M1 to M2 TAMs has emerged to be a prevailing parameter to evaluate this polarization phenomena for clinical application. This mini-review focuses on recent studies exploring clinical significance of M1/M2 TAM ratio in human cancer tissue and critically evaluates the technicalities and challenges in quantifying this parameter for routine clinical practice. Immunohistochemistry appears to be the preferred methodology for M1/M2 TAM evaluation as it is readily available in clinical laboratories, albeit with certain limitations. Recommendations are made to standardize the quantification of TAMs for better transition into clinical practice and for better comparison among studies in various populations of patients and cancer types.

Keywords: CD163; CD68; M1; M2; cancer; immunohistochemistry; tumor-associated macrophages.

Figure 1

Illustration of how M1 and M2 TAMs are activated, their respective functions, and the common IHC markers used to distinguish the two phenotypes in tissue samples. M1 TAMs are activated by toll-like receptors (TLRs) or Th1 cytokines, such as tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and colony stimulating factor 2 (CSF2). They are pro-inflammatory, microbicidal and have anti-tumoral effect. HLA-DR, CD11c, CD86, iNOS, and pSTAT1 are some of the common IHC markers used to identify M1 TAMs. M2 TAMs are activated by IL4, IL10, IL13, transforming growth factor beta (TGFβ) or prostaglandin E2 (PGE2). They are anti-inflammatory, promotes wound healing, and are pro-tumoral. CD163, CD204, CD206, VEGF, and cMAF are some of the IHC markers used to distinguish M2 TAMs.