Key Players of the Immunosuppressive Tumor Microenvironment and Emerging Therapeutic Strategies

Abstract

The tumor microenvironment (TME) is a complex, dynamic battlefield for both immune cells and tumor cells. The advent of the immune checkpoint inhibitors (ICI) since 2011, such as the anti-cytotoxic T-lymphocyte associated protein (CTLA)-4 and anti-programmed cell death receptor (PD)-(L)1 antibodies, provided powerful weapons in the arsenal of cancer treatments, demonstrating unprecedented durable responses for patients with many types of advanced cancers. However, the response rate is generally low across tumor types and a substantial number of patients develop acquired resistance. These primary or acquired resistance are attributed to various immunosuppressive elements (soluble and cellular factors) and alternative immune checkpoints in the TME. Therefore, a better understanding of the TME is absolutely essential to develop therapeutic strategies to overcome resistance. Numerous clinical studies are underway using ICIs and additional agents that are tailored to the characteristics of the tumor or the TME. Some of the combination treatments are already approved by the Food and Drug Administration (FDA), such as platinum-doublet chemotherapy, tyrosine kinase inhibitor (TKI) -targeting vascular endothelial growth factor (VEGF) combined with anti-PD-(L)1 antibodies or immuno-immuno combinations (anti-CTLA-4 and anti-PD-1). In this review, we will discuss the key immunosuppressive cells, metabolites, cytokines or chemokines, and hypoxic conditions in the TME that contribute to tumor immune escape and the prospect of relevant clinical trials by targeting these elements in combination with ICIs.

Keywords: cancer; clinical trials; immune checkpoint inhibitors; immune escape; immunotherapy; tumor microenvironment.

FIGURE 1

(A) A diagram depicting the restoration of effector T cell antitumor activities by immune checkpoint inhibitors such as the anti-programmed cell death protein 1 (PD-1) monoclonal antibody. T cells secrete cytokines such as tumor necrosis factor (TNF) -α and interferon (IFN) -γ to generate an inflammatory environment while releasing granules with perforin and granzyme B to induce tumor apoptosis. (B) Immunosuppression in the TME. Tumor cells release chemokines such as C-C motif ligands (CCLs) and C-X-C motif ligands (CXCLs), which interact with C-C motif receptors (CCRs) and C-X-C motif receptors (CXCRs), respectively, to recruit immunosuppressive cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), M2-like tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs) into the tumor microenvironment. Tregs secrete interleukin (IL)-35 and IL-10 to induce the upregulation of inhibitory receptors such as PD-1, T cell immunoglobulin and mucin-domain containing 3 (TIM3), T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), and lymphocyte activation gene 3 (LAG3). The binding of anti-PD-1 mAb to Tregs has the potential to increase its suppressive functions. The engagement of inhibitory receptors impairs T cell antitumor activities by suppressing IFN-γ and inducing T cell exhaustion by promoting its secretion of anti-inflammatory cytokines. M2-like TAMs are induced by the prostaglandin E2 (PGE2)—abundant TME to upregulate the expression of arginase 1 (Arg1) and IL-10, and secrete factors like IL-6 and vascular epithelial growth factor (VEGF) to promote tumor immune escape and migration. Tumors recruit both immature myeloid cells (IMCs) and MDSCs into the TME, where the expansion of IMCs into MDSCs are induced by factors such as IL-1β, IL-4, IL-10, IL-13, and IFN-γ. MDSCs exert immunosuppression via the expression of the TIM3 ligand galectin-9, inducible nitric oxide synthase (iNOS), and nicotinamide adenine dinucleotide phosphate oxidase (NOX) 2. iNOS and NOX2 produce nitric oxide and reactive oxygen species, which are detrimental to proper immune functions. CAFs secrete a variety of factors such as CXCL5, CXCL12, CCL2, and leukemia inhibitory factor (LIF), which serve immunosuppressive functions. CAFs are additionally capable of inducing T cell death with Fas ligand (FasL). CCR: C-C motif receptor; CD: cluster of differentiation; PD-L1: programmed cell death protein ligand 1.