Metastatic pancreatic neuroendocrine tumors feature elevated T cell infiltration

Abstract

Pancreatic neuroendocrine tumors (PNETs) are malignancies arising from the islets of Langerhans. Therapeutic options are limited for the over 50% of patients who present with metastatic disease. We aimed to identify mechanisms to remodel the PNET tumor microenvironment (TME) to ultimately enhance susceptibility to immunotherapy. The TMEs of localized and metastatic PNETs were investigated using an approach that combines RNAsequencing, cancer and T cell profiling, and pharmacologic perturbations. RNA-sequencing analysis indicated that the primary tumors of metastatic PNETs showed significant activation of inflammatory and immune-related pathways. We determined that metastatic PNETs featured increased numbers of tumor-infiltrating T cells compared to localized tumors. T cells isolated from both localized and metastatic PNETs showed evidence of recruitment and antigendependent activation, suggestive of an immune-permissive microenvironment. A computational analysis suggested that vorinostat, a histone deacetylase inhibitor, may perturb the transcriptomic signature of metastatic PNETs. Treatment of PNET cell lines with vorinostat increased chemokine CCR5 expression by NFκB activation. Vorinostat treatment of patient-derived metastatic PNET tissues augmented recruitment of autologous T cells, which was substantiated in a mouse model of PNET. Pharmacologic induction of chemokine expression may represent a promising approach for enhancing the immunogenicity of metastatic PNET TMEs.

Combined deletion of MEN1, ATRX and PTEN triggers development of high-grade pancreatic neuroendocrine tumors in mice

“…Vol:. ( 1234567890 www.nature.com/scientificreports/ Finally, we sought to investigate similarities in overall gene expression profiles of MAP tumors and PanNET samples representing localized and metastatic disease 44 . Spearman's correlation analysis revealed the statistically significant (p < 0.01) strong positive correlation (Spearman's correlation coefficient > 0.7) between MAP and human PanNET transcriptomes (Fig.…”

“…Protein bands were visualized using Amersham ECL or Amersham ECL Prime western blotting detection reagent. Previously reported RNA-seq datasets of human PanNETs 44 were obtained from Gene Expression Omnibus (accession no. GSE178398) and RIP-Tag2 mouse model 45 from the ZENODO database (access: doi.org/https:// doi.…”

B cells present a double-sided effect in digestive system tumors: a review for tumor microenvironment

“…TLS, which are anomalous lymphoid organs that emerge in non-lymphoid tissues, are commonly detected in a diverse range of persistent inflammatory ailments such as inflammatory diseases, autoimmune and infectious diseases, transplanted organs, and tumors ( 30 ). TLS is comprised of B cells, enveloped by T cells, and additionally encompasses TFH, dendritic cells, fibroblasts, blood vessels, and other cellular and structural components ( 31 ).…”

Spatial and temporal heterogeneity of digestive neuroendocrine neoplasms

“…47,48 Yet, it seems that the immune microenvironment may evolve, since metastatic PanNETs have a more immune-tolerant infiltrate that could represent a potential target. 49 In addition to the immune infiltrate, the fibrotic stroma and the vasculature are also remodeled though NET progression with an increase in extracellular matrix deposition and a decrease in vessel density associated with NEN aggressivity, which may be assessed by imaging. 50,51 Non-invasive assessment of intratumor heterogeneity is challenging but could be performed using radiomics approaches.…”