# Immune Cell Molecular Pharmacodynamics of Lanreotide in Relation to Treatment Response in Patients with Gastroenteropancreatic Neuroendocrine Tumors

## TL;DR

This study explores how lanreotide affects the immune system in patients with neuroendocrine tumors, finding immune-related changes linked to treatment response.

## Contribution

The study reveals novel immune pathways influenced by lanreotide in vivo that correlate with treatment response in NET patients.

## Key findings

- Lanreotide reduces wnt, TCR, and NF-kB signaling in CD8+ T cells in responders compared to non-responders.
- Responders show reduced cytokine/chemokine signaling but increased ubiquitination and proteasome degradation gene effects.
- In vivo immune effects of lanreotide correlate with clinical response, not observed in in vitro studies.

## Abstract

Somatostatin analogs like lanreotide are considered first-line agents for the treatment of gastroenteropancreatic neuroendocrine tumors (NET). Although its effects on tumor proliferation and hormonal regulation are somewhat understood, its influence on the immune system has not been well elucidated. We used a double-pronged approach to understand the role of lanreotide in immune system regulation in healthy donor T cells in vitro as well as in vivo in cells obtained from 17 NET patients. We looked at cytokine signaling and differential gene expression to elucidate lanreotide’s role in the treatment of NET through additional novel immune pathways.

The CLARINET trial led to the approval of lanreotide for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (NETs). It is hypothesized that lanreotide regulates proliferation, hormone synthesis, and other cellular functions via binding to somatostatin receptors (SSTR1–5) present in NETs. However, our knowledge of how lanreotide affects the immune system is limited. In vitro studies have investigated functional immune response parameters with lanreotide treatment in healthy donor T cell subsets, encompassing the breadth of SSTR expression, apoptosis induction, cytokine production, and activity of transcription factor signaling pathways. In our study, we characterized in vitro immune mechanisms in healthy donor T cells in response to lanreotide. We also studied the in vivo effects by looking at differential gene expression pre- and post-lanreotide therapy in patients with NET. Immune-focused gene and protein expression profiling was performed on peripheral blood samples from 17 NET patients and correlated with clinical response. In vivo, lanreotide therapy showed reduced effects on wnt, T cell receptor (TCR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling in CD8+ T cells in responders compared to non-responders. Compared to non-responders, responders showed reduced effects on cytokine and chemokine signaling but greater effects on ubiquitination and proteasome degradation genes. Our results suggest significant lanreotide pharmacodynamic effects on immune function in vivo, which correlate with responses in NET patients. This is not evident from experimental in vitro settings.