Defining Tumor Microenvironment as a Possible Target for Effective GEP-NENs Immunotherapy—A Systematic Review

Abstract

Neuroendocrine neoplasms (NENs) are a heterogenous and recurrent group of malignancies originating from neuroendocrine secretory cells diffused on all parts of the human body. Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) account for most NENs. Considering the abundance of possible origins, locations, and tumor specifications, there is still no consensus about optimal treatment options for these neoplasms. In light of the escalating immunotherapeutic approaches, it is crucial to define indications for such therapy in GEP-NETs. Bearing in mind the significance of pathophysiological mechanisms and tumor microenvironment (TME) impact on carcinogenesis, defining TME structure and correlation with the immune system in GEP-NETs appears essential. This paper aimed to assess the characterization of the tumor immune microenvironment for a better understanding of the possible therapeutic options in GEP-NETS. The authors performed a systematic review, extracting papers from the PubMed, Web of Science, and Scopus databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Among 3800 articles identified through database searching, 292 were assessed for eligibility. Ultimately, 28 articles were included in the qualitative synthesis. This paper sums up the research on the immune cell infiltrates, immune checkpoint expression, cytokine profile, neoangiogenesis, and microbiome in the TME of GEP-NETs.

Lung NETs and GEPNETs: One Cancer with Different Origins or Two Distinct Cancers?

“…It has been observed that the expression of IFNγ-associated genes and intratumoral T-cell infiltration are low in both NET G1/G2 and NET G3/NEC. While neuroendocrine carcinomas (NECs) exhibit hot immune microenvironments with an abundance of tumor-infiltrating lymphocytes (TILs), neuroendocrine tumors (NETs) possess a cold immune microenvironment with fewer TILs [ 43 ]. Among the comparatively well-differentiated GEP-NETs, pancreatic NETs exhibited higher TILs, PD-1, and PD-L1 expression levels than non-pancreatic NENs.…”