Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)–dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor–bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell–dependent manner. These data provide a rationale for targeting macrophage recruitment/ response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach.

Macrophages are critical mediators of tissue homeostasis, with tumors distorting this proclivity to stimulate proliferation, angiogenesis, and metastasis. This had led to an interest in targeting macrophages in cancer, and preclinical studies have demonstrated efficacy across therapeutic modalities and tumor types. Much of the observed efficacy can be traced to the suppressive capacity of macrophages, driven by microenvironmental cues such as hypoxia and fibrosis. As a result, tumor macrophages display an ability to suppress T cell recruitment and function as well as regulate other aspects of tumor immunity. With the increasing impact of cancer immunotherapy, macrophage targeting is now being evaluated in this context. Here we will discuss the results of clinical trials and the future of combinatorial immunotherapy.

How neoplastic cells respond to therapy is not solely dependent on the complexity of genomic aberrations they harbor, but is also regulated by numerous dynamic properties of the tumor microenvironment. Identifying and targeting critical pathways that improve therapeutic efficacy by bolstering anti-tumor immune responses holds great potential for improving outcomes and impacting long-term patient survival. Macrophages are key regulators of homeostatic tissue and tumor microenvironments; thus therapeutics impacting macrophage presence and/or bioactivity have shown promise in preclinical models, and are now being evaluated in the clinic. This review discusses the molecular/cellular pathways thus far identified whereby macrophages mediate therapeutic responses.

Summary Blockade of colony-stimulating factor-1 (CSF-1) limits macrophage infiltration and improves response of mammary carcinomas to chemotherapy. Herein we identify interleukin (IL)-10 expression by macrophages as the critical mediator of this phenotype. Infiltrating macrophages were the primary source of IL-10 within tumors, and therapeutic blockade of IL-10 receptor (IL-10R) was equivalent to CSF-1 neutralization in enhancing primary tumor response to paclitaxel and carboplatin. Improved response to chemotherapy was CD8+ T cell-dependent, however IL-10 did not directly suppress CD8+ T cells or alter macrophage polarization. Instead, IL-10R blockade increased intratumoral dendritic cell expression of IL-12, which was necessary for improved outcomes. In human breast cancer, expression of IL12A and cytotoxic effector molecules were predictive of pathological complete response rates to paclitaxel.

Of the multiple unique stromal cell types common to solid tumors, tumor-associated macrophages (TAMs) have been recognized as significant for fostering tumor progression. The protumor properties of TAMs are derived from their ability to regulate angiogenic programming, provide soluble mediators to malignant cells for proliferation, survival and invasion, and for directly and indirectly suppressing activity of cytotoxic T cells. These varied activities are dependent on the polarization state of TAMs that is regulated in part by local concentrations of cytokines and chemokines, as well as varied interactions of TAMs with normal and degraded components of the extracellular matrix. Targeting molecular pathways regulating TAM polarization holds great promise for anti-cancer therapy.