Tumor-associated macrophages: Prognostic and therapeutic targets for cancer in humans and dogs

Abstract

Macrophages are ancient, phagocytic immune cells thought to have their origins 500 million years ago in metazoan phylogeny. The understanding of macrophages has evolved to encompass their foundational roles in development, homeostasis, tissue repair, inflammation, and immunity. Notably, macrophages display high plasticity in response to environmental cues, capable of a strikingly wide variety of dynamic gene signatures and phenotypes. Macrophages are also involved in many pathological states including neural disease, asthma, liver disease, heart disease, cancer, and others. In cancer, most tumor-associated immune cells are macrophages, coined tumor-associated macrophages (TAMs). While some TAMs can display anti-tumor properties such as phagocytizing tumor cells and orchestrating an immune response, most macrophages in the tumor microenvironment are immunosuppressive and pro-tumorigenic. Macrophages have been implicated in all stages of cancer. Therefore, interest in manipulating macrophages as a therapeutic strategy against cancer developed as early as the 1970s. Companion dogs are a strong comparative immuno-oncology model for people due to documented similarities in the immune system and spontaneous cancers between the species. Data from clinical trials in humans and dogs can be leveraged to further scientific advancements that benefit both species. This review aims to provide a summary of the current state of knowledge on macrophages in general, and an in-depth review of macrophages as a therapeutic strategy against cancer in humans and companion dogs.

Large granular lymphocyte lymphoma in 65 dogs (2005–2023)

“…It is possible some monocytes detected on haematology were actually myeloid‐derived suppressor cells, comprising immature monocytes and neutrophils, which suppress T‐cell and NK‐cell mediated antitumour immunity 38,39 . Monocytosis could also be due to increased tumour production of monocyte chemotactic protein‐1 (MCP‐1), known to be increased in lymphoma‐bearing dogs 39 ; MCP‐1 can recruit tumour‐associated macrophages which are associated with poorer outcomes in many human cancers due to their pro‐angiogenic and immunosuppressive effects 39,40 . Thrombocytopenia and neutropenia were associated with reduced likelihood of response to chemotherapy.…”

Immunotherapy Innovations in the Fight against Osteosarcoma: Emerging Strategies and Promising Progress

“…Additionally, the CAR-M technology presents a novel therapeutic approach for enhancing the macrophages’ ability to phagocytose cancer cells and present antigens, thereby enabling macrophages against cancer [ 125 ]. Engineered CAR-Ms have resulted in increase of anti-tumor cytokines, such as IL6, and chemokines, such as CXCL18, in the OS-TME [ 141 , 142 ]. The production of these beneficial cytokines fosters a shift from a cold OS-TME towards a hot OS-TME [ 143 ].…”

From Dual Roles to Translational Challenges: Unpacking the Complexities of Tumor-Associated Macrophages in Cancer Progression and Therapy

“…TAMs exhibit a high degree of heterogeneity and require biomarkers that can accurately distinguish TAMs from other immune cells in the TME [7,40,67,68]. In addition, identifying biomarkers that can distinguish between different subsets of TAMs (such as M1-type and M2-type) could help to guide the development of TAM-targeted therapies that selectively modulate specific TAM subsets [5,129,139]. The development of non-invasive imaging and diagnostic techniques that can identify and quantify TAMs in tumors could also help to develop and monitor TAM-targeted therapies [140][141][142].…”