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Macrophages are crucial innate immune cells that maintain tissue homeostasis and defend against pathogens; however, their infiltration into tumors has been associated with adverse outcomes. Tumor-associated macrophages (TAMs) represent a significant component of the inflammatory infiltrate in breast tumors, and extensive infiltration of TAMs has been linked to poor prognosis in breast cancer. Here, we detail how TAMs impede a productive tumor immunity cycle by limiting antigen presentation and reducing activation of cytotoxic T lymphocytes (CTLs) while simultaneously supporting tumor cell survival, angiogenesis, and metastasis. There is an urgent need to overcome TAM-mediated immune suppression for durable anti-tumor immunity in breast cancer. To date, failure to fully characterize TAM biology and classify multiple subsets has hindered advancement in therapeutic targeting. In this regard, the complexity of TAMs has recently taken center stage owing to their subset diversity and tightly regulated molecular and metabolic phenotypes. In this review, we reveal major gaps in our knowledge of the functional and phenotypic characterization of TAM subsets associated with breast cancer, before and after treatment. Future work to characterize TAM subsets, location, and crosstalk with neighboring cells will be critical to counteract TAM pro-tumor functions and to identify novel TAM-modulating strategies and combinations that are likely to enhance current therapies and overcome chemo- and immuno-therapy resistance., Competing Interests: JG is a consultant for Glaxo-Smith Kline (GSK), Codagenix, Verseau, Kymera, and Array BioPharma and receives sponsored research support from GSK, Array BioPharma, and Eli Lilly. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mehta, Kadel, Townsend, Oliwa and Guerriero.)

The complexity of T cell activation to maintain homeostasis and provide host defense is highlighted by the intricate step-wise process which is coordinated by multiple cell types. Crucial to T cell activation is the requirement of antigen-presenting cells (APCs) such as macrophages at each step of the activation and effector stages. Macrophages are central regulators in T cell activation and are involved in each step including initiating the series of events leading to T cell activation. Macrophages identify and present foreign antigens in classes I and II major histocompatibility complexes (MHC) to T cells, which recognize the MHC-antigen complex through their T cell receptor. This initial step is all in vain if additional costimulatory and cytokine signaling does not occur concurrently. Macrophages can mediate and provide the required costimulatory signaling and cytokine secretion required for effective T cell activation. While other cell types, especially other APCs, may be capable of playing a role during different stages of T cell activation, this review will focus on how macrophages can modulate T cell activation and effector function. This is in no way an attempt to minimize the role of other APCs but instead to bring to light to the role macrophages can play during this process. Here, the role macrophages play in cancer to either activate or inhibit T cells based on macrophage phenotype, costimulatory molecules, and cytokine secretion is highlighted as an example of how macrophages can significantly alter T cell activation and effector function in human disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Macrophages are present in all vertebrate tissues and have emerged as multifarious cells with complex roles in development, tissue homeostasis, and disease. Macrophages are a major constituent of the tumor microenvironment, where they either promote or inhibit tumorigenesis and metastasis depending on their state. Successful preclinical strategies to target macrophages for anticancer therapy are now being evaluated in the clinic and provide proof of concept that targeting macrophages may enhance current therapies; however, clinical success has been limited. This review discusses the promise of targeting macrophages for anticancer therapy, yet highlights how much is unknown regarding their ontogeny, regulation, and tissue-specific diversity. Further work might identify subsets of macrophages within different tissues, which could reveal novel therapeutic opportunities for anticancer therapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.