Targeting tumor-associated macrophages to synergize tumor immunotherapy

Abstract

The current treatment strategies in advanced malignancies remain limited. Notably, immunotherapies have raised hope for a successful control of these advanced diseases, but their therapeutic responses are suboptimal and vary considerably among individuals. Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and are often correlated with poor prognosis and therapy resistance, including immunotherapies. Thus, a deeper understanding of the complex roles of TAMs in immunotherapy regulation could provide new insight into the TME. Furthermore, targeting of TAMs is an emerging field of interest due to the hope that these strategies will synergize with current immunotherapies. In this review, we summarize recent studies investigating the involvement of TAMs in immune checkpoint inhibition, tumor vaccines and adoptive cell transfer therapies, and discuss the therapeutic potential of targeting TAMs as an adjuvant therapy in tumor immunotherapies.

Fig. 1

Classification of current tumor immunotherapies. The current tumor immunotherapies can be roughly divided into three types: a checkpoint inhibitors, including anti-PD-1/L1 and anti-CTLA-4 monoclonal antibodies; (b) tumor vaccines, including various dendritic cell-based vaccines and oncolytic virus-based vaccines; and (c) adoptive cell transfer, including CAR-T or TCR-engineered T cells. The antigens released from necrotic tumor cells during surgery, locoregional therapy, chemotherapy or targeted therapy enhance the immune recognition of tumor cells

Fig. 2

TAMs as regulators of tumor immunotherapies. TAMs exert their distinct regulatory functions in response to different immunotherapies: a In checkpoint inhibitor therapy, TAMs can suppress effective T cells directly via the expression of various checkpoint molecules and immunosuppressive cytokines and indirectly through crosstalk with Tregs and hijacking of anti-PD-1 antibodies. b In tumor vaccine therapy, TAMs can inhibit the antigen-presenting efficiency of dendritic cells; c In adoptive cell transfer therapy, TAMs prevent immune infiltration via build up the highly fibrotic and angiogenic TME

Fig. 3

TAM-targeted Strategies in Tumors. TAM-targeted strategies can be roughly divided as follows: a elimination of macrophages already present in tumor tissue; (b) inhibition of monocyte/macrophage recruitment; (c) reeducation of TAMs toward an “immune-supportive” phenotype characterized by restored phagocytic and antigen presenting ability