Myeloid immunosuppression and immune checkpoints in the tumor microenvironment

Abstract

Tumor-promoting inflammation and the avoidance of immune destruction are hallmarks of cancer. While innate immune cells, such as neutrophils, monocytes, and macrophages, are critical mediators for sterile and nonsterile inflammation, persistent inflammation, such as that which occurs in cancer, is known to disturb normal myelopoiesis. This disturbance leads to the generation of immunosuppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Due to their potent suppressive activities against effector lymphocytes and their abundance in the tumor microenvironment, immunosuppressive myeloid cells act as a major barrier to cancer immunotherapy. Indeed, various therapeutic approaches directed toward immunosuppressive myeloid cells are actively being tested in preclinical and clinical studies. These include anti-inflammatory agents, therapeutic blockade of the mobilization and survival of myeloid cells, and immunostimulatory adjuvants. More recently, immune checkpoint molecules expressed on tumor-infiltrating myeloid cells have emerged as potential therapeutic targets to redirect these cells to eliminate tumor cells. In this review, we discuss the complex crosstalk between cancer-related inflammation and immunosuppressive myeloid cells and possible therapeutic strategies to harness antitumor immune responses.

Keywords: immune checkpoint; inflammation; innate immunity; macrophage; myeloid.

Fig. 1

The link between cancer-related inflammation and myeloid immunosuppression. Cancer-related inflammation is orchestrated by intrinsic pathways (driven by oncogenes) and extrinsic pathways (by interaction between DAMPs and PRRs in environmental cells). A wide variety of growth factors and proinflammatory cytokines can alter myelopoiesis in the bone marrow, leading to the generation of immature myeloid cells with potent immunosuppressive activities (i.e., MDSCs). In response to chemokines, MDSCs are subsequently recruited into tumor tissues, where they further undergo dynamic alteration (e.g., differentiation into TAMs from monocytic MDSCs). MDSCs and TAMs act as a key barrier for antitumor immunity. In addition to monocytes and granulocytes, erythroblast-like cells (called Ter-cells) emerge in spleens under tumor-bearing conditions

Fig. 2

Potential immune checkpoint molecules on myeloid cells. a Tumor-associated macrophages and dendritic cells (DCs) express several T cell immune checkpoints and their ligands. While the trans interaction between PD-L1 on myeloid cells and PD-1 on T cells critically regulates T cell activation, the cis interaction between PD-L1 and B7-1 on antigen-presenting cells competitively inhibits the trans interaction. TAMs and DCs also express PD-1, which negatively regulates innate immune responses. TIM-3 on DCs also negatively regulates cytokine production, either directly by interacting with galectin-9 on tumor cells or indirectly by the sequestration of the HMGB1-nucleic acid complex (ligands for RAGE and TLRs). b ITIM-containing receptors SIRPα, LILRB1, and Siglec-10 have emerged as key receptors that negatively regulate cellular phagocytosis through the recognition of CD47, MHC class 1, and CD24, respectively. Note that PD-1 on macrophages is also known to regulate phagocytosis. c Through the recognition of certain ligands in the TME, several scavenger receptors might contribute to metabolic switching toward protumor TAMs, given that genetic ablation or pharmacological inhibition of these receptors can direct TAMs into antitumor phenotypes