Macrophage targeting in cancer.

Martha Lopez‐Yrigoyen,Jeffrey W Pollard,Luca Cassetta

doi:10.1111/nyas.14377

Martha Lopez‐Yrigoyen, Jeffrey W Pollard + Show 1 more

Open Access

https://doi.org/10.1111/nyas.14377

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Abstract

Tumorigenesis is not only determined by the intrinsic properties of cancer cells but also by their interactions with components of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are among the most abundant immune cells in the TME. During initial stages of tumor development, macrophages can either directly promote antitumor responses by killing tumor cells or indirectly recruit and activate other immune cells. As genetic changes occur within the tumor or T helper 2 (TH 2) cells begin to dominate the TME, TAMs begin to exhibit an immunosuppressive protumor phenotype that promotes tumor progression, metastasis, and resistance to therapy. Thus, targeting TAMs has emerged as a strategy for cancer therapy. To date, TAM targeting strategies have focused on macrophage depletion and inhibition of their recruitment into the TME. However, these strategies have shown limited therapeutic efficacy, although trials are still underway with combination therapies. The fact that macrophages have the potential for antitumor activity has moved the TAM targeting field toward the development of TAM-reprogramming strategies to support this antitumor immune response. Here, we discuss the various roles of TAMs in cancer therapy and their immunosuppressive properties, as well as implications for emerging checkpoint inhibitor-based immunotherapies. We review state-of-the-art TAM-targeting strategies, focusing on current ones at the preclinical and clinical trial stages that aim to reprogram TAMs as an oncological therapy.

Highlights

Tumor-associated macrophages (TAMs) are among the most abundant immune cells in the tumor microenvironment (TME).[1,2,3] Originally, they were thought to be antitumoral, owing to their ability to kill tumor cells in vitro.[4,5,6] at the earliest stages of tumor onset, the immune system may promote activation of T cells and macrophages to clear tumor cells.[7]
High infiltration of TAMs correlates with poor prognosis and reduced patient survival in several different types of cancer, including human breast, gastric, oral, ovarian, bladder, and thyroid cancers, non-small cell lung carcinoma (NSCLC), and Hodgkin’s lymphoma.[19,20,21]. Consistent with those correlative data, in vivo experiments in mouse models of cancer have indicated that TAMs are protumoral. These conclusions were derived from genetic ablation of Csf[1] and, thereby, elimination of macrophages in a mammary carcinoma mouse model, which resulted in delayed tumor development and reduced pulmonary metastasis.[22]
The protumor roles of TAMs reported in this review strongly support the idea that targeting macrophages in cancer is a promising therapeutic strategy

Summary

Introduction

Tumor-associated macrophages (TAMs) are among the most abundant immune cells in the tumor microenvironment (TME).[1,2,3] Originally, they were thought to be antitumoral, owing to their ability to kill tumor cells in vitro.[4,5,6] at the earliest stages of tumor onset, the immune system may promote activation of T cells and macrophages to clear tumor cells.[7].

Results

Conclusion