Immunosuppressive Mechanisms of Tumor-Associated Macrophages: Bioinformatic Analyses and Targeting

In recent years, the treatment of various cancers with immunotherapeutic strategies has revolutionized the classical treatments with chemotherapy or radiation. Such immunotherapeutic strategies are effective only in a subset of cancer patients who were unresponsive to conventional therapies and are not generalized to all cancer types. Several mechanisms have been reported that underlie the failure of the natural anti-tumor immunity or the administered immunotherapeutic agents in the treatment of cancer. Among these mechanisms is the pivotal role played by the immunosuppressive tumor microenvironment (TME). The TME is complex and consists of the stroma, blood vessels, and several cell types that have a direct relationship with the tumor as well as the tumor-relationship with the TME. Among the immunosuppressive cells in the TME are the tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), T regulatory cells (Tregs), and cancer-associated fibroblasts (CAFs). These cells altogether inhibit both innate and the adaptive anti-tumor immune responses. Noteworthy, TAMs represent > 50 % of all the infiltrating cells in the TME and their frequencies correlate with poor prognoses in many cancers. The depletion or inactivation of TAMs has been reported to restore, in large part, the anti-tumor immune response in several cancers. In this review, we discuss (i) the interrelationship between TAMs and cancer stem cells, (ii) the various mechanisms by which TAMs suppress the immune response [e.g., expression of inhibitory receptors and ligands, secretion of immunosuppressive cytokines, secretion of chemokines, secretion of arginase 1, secretion of IDO1 and expression of the triggering receptor expressed on myeloid cells (TREM)], and (iii) targeting TAMs for immunotherapy (e.g., depletion of TAMs, killing of TAMs, inhibition of TAM recruitment, reprogramming of TAMs, targeting Toll-like receptors, inhibition of PI3K gamma, HDAC inhibitors, and inhibition of specific miRNA activities, and targeting TREM and exosomes). In addition, we present bioinformatic analyses that demonstrated that (i) TAM infiltration into many cancers correlated with poor survival (ii) the TAM infiltration was associated with the clinical stages of the cancer and (iii) there is a strong correlation between the TAM infiltrates and various immunosuppressive gene products. Although many clinical studies are underway to inhibit the immunosuppressive functions of TAMs through a variety of mechanisms, by either targeting TAMs alone or in combination with other therapeutics, we present various perspectives that need to be considered for the successful translational application of TAMs targeting alone or in combination with other therapies in the clinic.