Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets

Abstract

Immunotherapies like the adoptive transfer of gene-engineered T cells and immune checkpoint inhibitors are novel therapeutic modalities for advanced cancers. However, some patients are refractory or resistant to these therapies, and the mechanisms underlying tumor immune resistance have not been fully elucidated. Immunosuppressive cells such as myeloid-derived suppressive cells, tumor-associated macrophages, tumor-associated neutrophils, regulatory T cells (Tregs), and tumor-associated dendritic cells are critical factors correlated with immune resistance. In addition, cytokines and factors secreted by tumor cells or these immunosuppressive cells also mediate the tumor progression and immune escape of cancers. Thus, targeting these immunosuppressive cells and the related signals is the promising therapy to improve the efficacy of immunotherapies and reverse the immune resistance. However, even with certain success in preclinical studies or in some specific types of cancer, large perspectives are unknown for these immunosuppressive cells, and the related therapies have undesirable outcomes for clinical patients. In this review, we comprehensively summarized the phenotype, function, and potential therapeutic targets of these immunosuppressive cells in the tumor microenvironment.

Keywords: Immunosuppressive cells; Immunosuppressive cellular cytokines; Immunotherapy; Tumor immune microenvironment.

Fig. 1

The immunosuppressive cells in tumor micro-environment. Immune cells infiltrate into the tumor microenvironment, interact with each other and tumor cells, and then harbor an immunosuppressive phenotype that is responsible for the immune escape of tumor cells and the following tumor progression. These immunosuppressive cells include MDSCs, M2-macrophages, Tregs, N2-TANs, mast cells, Bregs, dendritic cells. They secrete cytokines like IL-2, IL-10, and TGF-β, growth factors like VEGF, the checkpoints ligands like PD-L1 or express checkpoints on the cell surface like PD-1, TIM-3 on Tregs, that negatively regulate the anti-tumor immune response, remodel the extracellular matrix, and promote the angiogenesis. As a result, these immunosuppressive cells and their interaction generate an immunosuppressive microenvironment and promote the proliferation, evasion, and migration of tumor cells

Fig. 2

The potential strategies to target MDSCs. MDSC is the main type of immunosuppressive cell in cancer. Strategies targeting MDSCs to reverse the immunosuppression include depleting the populations of MDSCs by targeting VEGFR and CD33, blocking the migration and recruitment of MDSCs into TME by targeting the CCR2 or CXCR1/2, inhibiting the activity of MDSCs by targeting PGE2 and IDO, promoting the differentiation of MDSCs by TLR agonists, and inhibiting the metabolism of MDSCs by targeting FATP2 and CPT1

Fig. 3

The potential targets of TAMs in cancer therapy. M2-type TAMs in TME mediate the immunosuppression and promote the growth of tumor cells, as well as the resistance of cancer to immunotherapy. Strategies targeting the TAMs to reverse the immunosuppression include depleting and blocking the recruitment of TAMs into TME by targeting the CCR2 or CXCR1/2, targeting the activation of TAMs by CD40 and TLR7/8, modulating the phagocytosis of TAMs by targeting SIRPα, LILRB1, and Siglec-10. Furthermore, with the development of adoptive cell therapy, CAR-M represents a novel strategy that applies modified macrophages by adding specific CAR to them, which enhances the phagocytosis of macrophages on tumor cells. Besides, other advantages of CAR-M are identified, such as the resistance of CAR-M being polarized to M2 type

Fig. 4

The currently proposed therapy based on TANs targeting. Neutrophil is the first responder to injury. However, the roles and importance of neutrophils in inducing the tumor progression as well as the generation of immunosuppressive microenvironment have been revealed recently. Strategies targeting the TANs to reverse the immunosuppression include depleting and blocking the recruitment of TANs into TME by targeting the CXCR1/2, CXCR4, and CSF-1R, inhibiting the functions of TANs by targeting VEGFR and PGE2, blocking the development of TANs by IL-17/IL-23 inhibitors, and reprogramming TANs by targeting TGF-β, NAMPT, and FATP2