Immune evasion in esophageal squamous cell cancer: From the perspective of tumor microenvironment

Abstract

Esophageal cancer (EC) is one of the most life-threatening malignancies worldwide. Esophageal squamous cell carcinoma (ESCC) is the dominant subtype, accounting for approximately 90% of new incident EC each year. Although multidisciplinary treatment strategies have advanced rapidly, patients with ESCC are often diagnosed at advanced stage and the long-term prognosis remains unsatisfactory. In recent decades, immunotherapy, such as immune checkpoint inhibitors (ICIs), tumor vaccines, and chimeric antigen receptor T-cell (CAR-T) therapy, has been successfully used in clinical practice as a novel therapy for treating tumors, bringing new hope to ESCC patients. However, only a small fraction of patients achieved clinical benefits due to primary or acquired resistance. Immune evasion plays a pivotal role in the initiation and progression of ESCC. Therefore, a thorough understanding of the mechanisms by which ESCC cells escape from anti-tumor immunity is necessary for a more effective multidisciplinary treatment strategy. It has been widely recognized that immune evasion is closely associated with the crosstalk between tumor cells and the tumor microenvironment (TME). TME is a dynamic complex and comprehensive system including not only cellular components but also non-cellular components, which influence hallmarks and fates of tumor cells from the outside. Novel immunotherapy targeting tumor-favorable TME represents a promising strategy to achieve better therapeutic responses for patients with ESCC. In this review, we provide an overview of immune evasion in ESCC, mainly focusing on the molecular mechanisms that underlie the role of TME in immune evasion of ESCC. In addition, we also discuss the challenges and opportunities of precision therapy for ESCC by targeting TME.

Keywords: esophageal squamous cell cancer; immune evasion; immunosuppression; immunotherapy; tumor microenvironment.

Figure 1

Immunosuppressive tumor microenvironment (TME) in esophageal squamous cell cancer (ESCC). TME is a dynamic complex and comprehensive system, composed of various cellular components and non-cellular components. ESCC cells are born to create an immunosuppressive milieu suppressing the proliferation and function of cytolytic NK and T cells directly and indirectly. ESCC, esophageal squamous cell cancer; CTL, cytotoxic T lymphocyte; NK, natural killer cell; MDSC, myeloid-derived suppressor cell; TAM, tumor-associated macrophage; CAF, cancer-associated fibroblast; Treg, regulator T cell; TAN, tumor-associated neutrophils; Th17, T helper cell 17; MHC-1, major histocompatibility class I; TCR, T cell receptor; KAR, killer activation receptor; KIR, killer inhibitory receptor; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; PD-L2, programmed cell death ligand 2; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; LAG-3, lymphocyte activation gene-3; TIM-3, T-cell immunoglobulin and mucin domain-containing protein-3; TIGIT, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain; TGF-β, transforming growth factor-β; IL, interleukin; CXCL, CXC motif chemokine ligand; CCL, CC motif chemokine ligand; CCR, CC motif chemokine receptor; IDO, indoleamine 2,3-dioxygenase; iNOS, inducible nitric oxide synthase-2; ROS, reactive oxygen species.