Molecular Pathways: Deciphering Mechanisms of Resistance to Macrophage-Targeted Therapies

Abstract

Tumor-associated macrophages (TAMs) are a major cellular component of numerous tumor types. TAM-targeted therapies include depletion strategies, inhibiting their effector functions or reprogramming toward an antitumorigenic phenotype, with varying degrees of efficacy. Here, we review preclinical and clinical strategies to target macrophages in cancer and discuss potential explanations for why some strategies are effective while other approaches have shown limited success. Clin Cancer Res; 23(4); 876-84. ©2016 AACR.

Figure 1. Diversity of macrophage-targeting strategies in cancer

(A) Rather than depleting macrophages, therapies aimed at reprogramming or re-educating M2-like macrophages to adopt anti-tumor M1-like phenotypes or enhanced antigen-presenting capacity have demonstrated survival benefits in preclinical models (16, 19, 30, 41, 67). (B) Most macrophage-targeted therapies are currently focused on CSF-1R inhibitors, which either deplete or reprogram macrophages depending on the context. For example, in brain tumors, CSF-1R inhibitors have been shown to reprogram macrophages towards an anti-tumor phenotype (16, 19), while in breast cancer CSF-1R inhibitors have been shown to reduce macrophage numbers and thereby improve responses to cytotoxic therapies (, –25). (C) Macrophages can be targeted to reprogram the immunosuppressive tumor microenvironment and consequently enhance anti-tumor T cell responses. For example, in models of pancreatic ductal adenocarcinoma, CD40 agonists have been shown to enhance antigen presentation through MHCII expression on myeloid cells, leading to enhanced anti-tumor outcomes (39), and CSF-1R inhibitors have yielded similar results (41). (D) Another strategy to target macrophages is to prevent their systemic mobilization and recruitment towards specific tissues through blockade of chemokine gradients. Two examples of well-characterized gradients of this nature are SDF1/CXCR4 (45, 46), and CCL2/CCR2 (–54). (E) Myeloid cells can be targeted by virtue of specific behaviors such as angiogenesis. For example, TIE-2-expressing monocytes/macrophages (TEMs) can be targeted in different cancer models via neutralizing TIE-2 or angiopoietins, to reduce vascularization of tumors (–60).