The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms

Abstract

Gastroenteropancreatic neuroendocrine neoplasms feature high heterogeneity. Neuroendocrine tumor cells are closely associated with the tumor microenvironment. Tumor-infiltrating immune cells are mutually educated by each other and by tumor cells. Immune cells have dual protumorigenic and antitumorigenic effects. The immune environment is conducive to the invasion and metastasis of the tumor; in turn, tumor cells can change the immune environment. These cells also form cytokines, immune checkpoint systems, and tertiary lymphoid structures to participate in the process of mutual adaptation. Additionally, the fibroblasts, vascular structure, and microbiota exhibit interactions with tumor cells. From bench to bedside, clinical practice related to the tumor microenvironment is also regarded as promising. Targeting immune components and angiogenic regulatory molecules has been shown to be effective. The clinical efficacy of immune checkpoint inhibitors, adoptive cell therapy, and oncolytic viruses remains to be further discussed in clinical trials. Moreover, combination therapy is feasible for advanced high-grade tumors. The regulation of the tumor microenvironment based on multiple omics results can suggest innovative therapeutic strategies to prevent tumors from succeeding in immune escape and to support antitumoral effects.

Keywords: angiogenesis; combination therapy; gastroenteropancreatic neuroendocrine neoplasms; immunotherapy; tumor microenvironment.

Figure 1

The tumor microenvironment atlas in gastroenteropancreatic neuroendocrine neoplasms.

Figure 2

The interplay between tumor cells and tumor microenvironment cells. Tumor microenvironment cells encompass and interact with tumor cells. They express some molecules on the cell surface to regulate the occurrence and development of tumor, and these molecules are also common targets related to the tumor microenvironment. CTLA-4: cytotoxic T-lymphocyte-associated protein 4; FGFR: fibroblast growth factor receptor; LAG-3: lymphocyte activation gene 3; MHC: major histocompatibility complex; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; PD-L2: programmed death-ligand 2; TCR: T cell receptor; TIGIT: T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain; TIM3: T cell immunoglobulin and mucin domain-containing protein 3; VEGFR: vascular endothelial growth factor receptor.