Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy

Abstract

Deleterious inflammation is a primary feature of breast cancer. Accumulating evidence demonstrates that macrophages, the most abundant leukocyte population in mammary tumors, have a critical role at each stage of cancer progression. Such tumor-associated macrophages facilitate neoplastic transformation, tumor immune evasion and the subsequent metastatic cascade. Herein, we discuss the dynamic process whereby molecular and cellular features of the tumor microenvironment act to license tissue-repair mechanisms of macrophages, fostering angiogenesis, metastasis and the support of cancer stem cells. We illustrate how tumors induce, then exploit trophic macrophages to subvert innate and adaptive immune responses capable of destroying malignant cells. Finally, we discuss compelling evidence from murine models of cancer and early clinical trials in support of macrophage-targeted intervention strategies with the potential to dramatically reduce breast cancer morbidity and mortality.

Figure 1

The progression of breast cancer can be highlighted through the relationship between the primary tumor and specialized immune cells, including monocytes and TAMs. The primary tumor is made up of a heterogeneous population of breast cancer cells, which can recruit monocytes from the blood stream via secretion of cytokines, CCL2 and CSF1. Once monocytes are recruited to the primary tumor, these cells can then in turn differentiate into TAMs. The TAMs can secrete EGF that binds to EGFR on the breast cancer cells. This positive-feedback loop between TAMs and breast cancer cells is essential for the progression and migration of breast cancer cells to distant sites of metastasis. Along with TAMs providing EGF to the breast cancer cells, they also secrete VEGF and IL-8 into the TME, which stimulates (1) angiogenesis; the formation of new blood vessels around the primary tumor that deliver oxygen and nutrients. Additionally, TAMs induce breast cancer cells to (2) migrate and enter the blood stream, allowing them to travel to distant metastatic sites in the body. Breast cancer cells can migrate to premetastatic niches in distal organs that harbor a set of TAMs, which allows for (3) metastasis to occur. Common sites of metastasis include lung and bone, pictured here, as well as brain, liver, and lymph nodes. TAMs found in the premetastatic niche of metastatic sites display different receptors than the TAMs interacting with the primary breast tumor. Breast cancer cells can interact with these premetastatic niche TAMs within the metastatic site and the positive-feedback loop that occurs between the primary tumor and TAMs starts anew. EGF, epidermal growth factor; TAM, tumor-associated macrophages; TME, tumor microenvironment.

Figure 2

Modes of TAM-mediated immunosuppression. Upon recruitment to mammary tumors, exposure to TME-derived factors skew macrophage function from tumoricidal to tumorigenic. Hypoxia, growth factors, and immunosuppressive cytokines present in the TME polarize tumor-infiltrating macrophages toward a trophic phenotype, resulting in the loss of cytotoxic ability and acquisition of tissue-repair/growth capability. Concomitantly, the metabolism of L-arginine, production of immunosuppressive cytokines and expression of inhibitory T-cell checkpoint regulators by TAMs serve to inhibit T-cell activation and subsequent tumor killing. Finally, through the production of potent chemoattractants, TAMs recruit cells which further suppress antitumor immunity including MDSCs, immature DCs, and Tregs. Together, these processes culminate to circumvent immunosurveillance and tumor-reactive immunity capable of eliminating mammary tumors. TAM, tumor-associated macrophages; TME, tumor microenvironment.