The Promise of Targeting Macrophages in Cancer Therapy

Abstract

Cancer therapy has developed around the concept of killing, or stopping the growth of, the cancer cells. Molecularly targeted therapy is the modern expression of this paradigm. Increasingly, however, the realization that the cancer has co-opted the normal cells of the stroma for its own survival has led to the concept that the tumor microenvironment (TME) could be targeted for effective therapy. In this review, we outline the importance of tumor-associated macrophages (TAM), a major component of the TME, in the response of tumors to cancer therapy. We discuss the normal role of macrophages in wound healing, the major phenotypes of TAMs, and their role in blunting the efficacy of cancer treatment by radiation and anticancer drugs, both by promoting tumor angiogenesis and by suppressing antitumor immunity. Finally, we review the many preclinical studies that have shown that the response of tumors to irradiation and anticancer drugs can be improved, sometimes markedly so, by depleting TAMs from tumors or by suppressing their polarization from an M1 to an M2 phenotype. The data clearly support the validity of clinical testing of combining targeting TAMs with conventional therapy. Clin Cancer Res; 23(13); 3241-50. ©2017 AACR.

Figure 1

Key roles of macrophages in the process of injury and repair. After wounding, repair proceeds in three phases: inflammation, proliferation and remodeling. Macrophages, which are predominantly M1 phenotype in the period of inflammation and then shift towards M2 in the remodeling phase, are influential drivers of each phase and impact endothelial, myoblast and fibroblast cellular functioning through release of a number of important cytokines and growth factors. Redrawn from Novak and Koh (32), with permission from Elsevier. EC endothelial cell, Fb fibroblast.

Figure 2. Representation of the tumor microenvironment before and after irradiation

Following irradiation and other anticancer agents the vasculature of the tumor is damaged leading to reduced tumor blood flow and increased hypoxia. This produces increased expression of HIF-1 and HIF-2, which results in increased expression of a diverse spectrum of cytokines, including stromal cell-derived factor-1 (SDF-1, CXCL2), producing greater recruitment and influx into the tumor of bone marrow derived monocytes which differentiate into TAMs. TEMs commonly associate with the vasculature, while CD68+ TAMs frequently localize to areas of severe hypoxia. Redrawn from Russell and Brown (83).