Bringing Macrophages to the Frontline against Cancer: Current Immunotherapies Targeting Macrophages

Abstract

Macrophages are found in all tissues and display outstanding functional diversity. From embryo to birth and throughout adult life, they play critical roles in development, homeostasis, tissue repair, immunity, and, importantly, in the control of cancer growth. In this review, we will briefly detail the multi-functional, protumoral, and antitumoral roles of macrophages in the tumor microenvironment. Our objective is to focus on the ever-growing therapeutic opportunities, with promising preclinical and clinical results developed in recent years, to modulate the contribution of macrophages in oncologic diseases. While the majority of cancer immunotherapies target T cells, we believe that macrophages have a promising therapeutic potential as tumoricidal effectors and in mobilizing their surroundings towards antitumor immunity to efficiently limit cancer progression.

Keywords: antitumor functions; macrophages; myeloid-targeted therapies; reprogramming.

Figure 1

Macrophages can act as key effectors in the cancer-immunity cycle. (1) TAMs can be reprogrammed to initiate the cycle by killing tumor cells through production of ROS/NO or in a contact-dependent manner. Cytotoxic TAMs would induce the release of tumor (neo-)antigens. (2–3) Phagocytosis of dead cancer cells by TAMs and transfer of cancer-associated antigens to dendritic cells (DC), in the TME, or after migration in the draining lymph nodes (LN). Subcapsular CD169⁺ macrophages in LN have also been reported to transfer cancer-associated antigens to DC. This leads to proficient activation of tumor-specific cytolytic CD8 T cells. (4) TAMs can secrete CXCL9, CXCL10, CXCL11, the ligands of CXCR3, and actively recruit tumor-specific CD8 T cells from the circulation. (5) TAMs can produce selective enzymes that loosen up the extracellular matrix, limit fibrosis, which in turn facilitates T cell infiltration deep within the tumor mass. (6) TAMs can potentiate the cytotoxic functions of NK and CD8 T cells. Altogether, this revisited model provides the rationale for targeting macrophages, which, by boosting different steps of the cancer-immunity cycle, will accelerate the generation of an anticancer response. This figure is adapted from [26,27].

Figure 2

(A) Describes the main known antitumor functions of macrophages in particular tumor cell killing and phagocytosis as well as recruitment and activation of immune cells in the TME. (B) Presents the current therapeutic strategies that target TAMs to induce anticancer responses. On the top left side are different approaches to kill macrophages or inhibit their recruitment in tumors. On the bottom left side are approaches to inhibit TAM protumor functions. On the right side are strategies to re-educate TAMs into antitumor effectors.

Figure 2

(A) Describes the main known antitumor functions of macrophages in particular tumor cell killing and phagocytosis as well as recruitment and activation of immune cells in the TME. (B) Presents the current therapeutic strategies that target TAMs to induce anticancer responses. On the top left side are different approaches to kill macrophages or inhibit their recruitment in tumors. On the bottom left side are approaches to inhibit TAM protumor functions. On the right side are strategies to re-educate TAMs into antitumor effectors.