Redefining Tumor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment

Abstract

The immunosuppressive status of the tumor microenvironment (TME) remains poorly defined due to a lack of understanding regarding the function of tumor-associated macrophages (TAMs), which are abundant in the TME. TAMs are crucial drivers of tumor progression, metastasis, and resistance to therapy. Intra-and inter-tumoral spatial heterogeneities are potential keys to understanding the relationships between subpopulations of TAMs and their functions. Antitumor M1-like and pro-tumor M2-like TAMs coexist within tumors, and the opposing effects of these M1/M2 subpopulations on tumors directly impact current strategies to improve antitumor immune responses. Recent studies have found significant differences among monocytes or macrophages from distinct tumors, and other investigations have explored the existence of diverse TAM subsets at the molecular level. In this review, we discuss emerging evidence highlighting the redefinition of TAM subpopulations and functions in the TME and the possibility of separating macrophage subsets with distinct functions into antitumor M1-like and pro-tumor M2-like TAMs during the development of tumors. Such redefinition may relate to the differential cellular origin and monocyte and macrophage plasticity or heterogeneity of TAMs, which all potentially impact macrophage biomarkers and our understanding of how the phenotypes of TAMs are dictated by their ontogeny, activation status, and localization. Therefore, the detailed landscape of TAMs must be deciphered with the integration of new technologies, such as multiplexed immunohistochemistry (mIHC), mass cytometry by time-of-flight (CyTOF), single-cell RNA-seq (scRNA-seq), spatial transcriptomics, and systems biology approaches, for analyses of the TME.

Pancreatic Cancers with High Grade Tumor Budding Exhibit Hallmarks of Diminished Anti-Tumor Immunity

“…Immunosuppressive TAMs can inhibit anti-tumor immunity through direct and indirect mechanisms. These include but are not limited to, inhibiting DC activation, direct suppression of T cells through checkpoint ligand expression and modulation of the vasculature [ 47 , 48 ] Conversely, putative M1 or immunostimulatory macrophages can induce DC maturation, T cell recruitment and display tumor cell killing [ 48 ]. In PDAC cases with HG versus LG tumor budding, we noted intriguing differences between the density of M1 and M2 macrophages.…”

Spatial Clustering of CD68+ Tumor Associated Macrophages with Tumor Cells is Associated with Worse Overall Survival in Metastatic Clear Cell Renal Cell Carcinoma

“…To our knowledge, this is the first analysis to investigate the clinical impact of TAM clustering in ccRCC.Secondarily, this analysis confirms previous work demonstrating the negative prognostic impact of TAM infiltration in ccRCC patients. It has been suggested that TAMs with an M2-like phenotype (markers CD163, CD204, and CD206) have a pro-tumor effect while M1-like TAMs (CD68, CD80, and CD86) may have an anti-tumor effect13 . However, this simplified dichotomy may not hold for all primary tumor sites, as high CD68+ TAM density has been identified as a negative prognostic indicator in breast and gastric cancer22,23 .…”

Potentiality of multiple modalities for single-cell analyses to evaluate the tumor microenvironment in clinical specimens

“…These findings www.nature.com/scientificreports/ demonstrate that scRNA-seq analysis is a highly-feasible platform for elucidating the complexity of the tumor microenvironments in small biopsy tumors. Recent advances in single-cell level analysis, such as scRNA-seq and CyTOF, allowed us to investigate the complexity of heterogeneity in TME in more detail, detecting small heterogeneous populations (e.g., TILs) at a high dimensional level 34,35 ; however, each of these platforms has strengths and weaknesses in their technical performance 36,37 . CyTOF, which has an advantage in higher throughput compared to scRNA-seq, could detect the targeting immune cell subsets more clearly using the ~ 40 selected antigen markers 19,38 .…”