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.

Divergent Resistance Mechanisms to Immunotherapy Explain Responses in Different Skin Cancers

“…We built macrophage inflammatory scores using genes that are either defined as “pro-inflammatory” or “anti-inflammatory” in Gene Ontology ( Figure S3 ) [ 31 , 32 ]. We chose not to emphasize the classical M1/M2 paradigm due to the increasing amount of evidence indicating that macrophages show more heterogeneity than two states, although we should note that some of these markers are included in our scoring scheme, and the M1 and M2 scores showed comparable trends ( Figure S3 ) [ 33 , 34 , 35 , 36 ]. In the melanoma dataset, we found that anti-inflammatory gene expression correlates well with the percentage of macrophages found in post-treatment non-responders, indicating that macrophages in the melanoma TME are involved in the refractory response to immunotherapy ( Figure 3 E).…”

“Re-educating” Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma

“…Importantly, limitations remain regarding the applicability of preclinical studies of TAMs as these studies often treat TAMs as a single homogeneous population and in vivo models may not fully recapitulate the diversity of the human tumor microenvironment, including the heterogeneity of human tumors ( 109 , 110 ). In addition, studies of TAMs in human tumors are limited by challenges from appropriate macrophage markers to standardization of quantification ( 111 ). Given this fluidity of polarization and limitations of current studies, we will discuss the polarization of TAMs throughout the review using the more simplified binary classification of M1 and M2 or M1-like and M2-like.…”

Development of Radiotracers for Breast Cancer—The Tumor Microenvironment as an Emerging Target

“…M2 macrophages repair and remodel injured tissue and are involved in debris scavenging and immune modulation. In cancer they act pro-angiogenic by secreting adrenomedullin and VEGFs and suppress the immune response in favor of the tumor [ 95 ].…”