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.

Exosomes‐mediated crosstalk between glioma and immune cells in the tumor microenvironment

“…Tumor cells in TME account for about 30% of the population. Immune cells within the tumor have been found to play either a tumor‐suppressing or promoting role, while some have a bidirectional regulatory role 144,145 . The functions of both tumor cells and immune cells in the TME are reciprocal, as the behavior of tumor cells is closely linked to tumorigenesis and progression, which then influences the biological behavior of stromal cells in the TME.…”

“…Immune cells within the tumor have been found to play either a tumor‐suppressing or promoting role, while some have a bidirectional regulatory role. 144 , 145 The functions of both tumor cells and immune cells in the TME are reciprocal, as the behavior of tumor cells is closely linked to tumorigenesis and progression, which then influences the biological behavior of stromal cells in the TME. Immunotherapy strategies have shown positive effects and potential cures for advanced high‐grade tumor patients; however, TME evolves dynamically through compensatory feedback mechanisms, blocking immunotherapeutic effects, generating drug resistance, and even tumor progression.…”

Checkpoint Markers and Tumor Microenvironment: What Do We Know?

“…To engage part in the process of mutual adaptation, these cells also secrete cytokines, immunological checkpoint systems, and tertiary lymphoid structures. Tumor cells interact with the fibroblasts, vascular system, and microbiome [ 47 ]. Other products within the TME, including B cells, fibroblast cells, myeloid lineage cells, and the vasculature, also play a part [ 48 ].…”

Infiltrating characteristics and prognostic value of tertiary lymphoid structures in resected gastric neuroendocrine neoplasm patients

“…Currently, studies combining tumor–node–metastasis (TNM) stages, WHO classifications and immune factors for the prognostic prediction of recurrence‐free survival (RFS) and (or) overall survival (OS) of patients with GNEN are scarce 8–10 . However, immune factors may play an important role in GNEN 11–13 . Thus, a comprehensive understanding of GNEN and combining the findings of GNEN immunity are urgently needed.…”

“… 8 , 9 , 10 However, immune factors may play an important role in GNEN. 11 , 12 , 13 Thus, a comprehensive understanding of GNEN and combining the findings of GNEN immunity are urgently needed.…”