The Microenvironment of Small Intestinal Neuroendocrine Tumours Contains Lymphocytes Capable of Recognition and Activation after Expansion.

Tobias Hofving,Joakim Karlsson,Jonas A. Nilsson,Frank Liang,Lisa M. Nilsson,Ola Nilsson,Ulf Yrlid

doi:10.3390/cancers13174305

Abstract

Simple SummaryThe body‘s immune system can recognize tumors because they often contain proteins that are either different from or more abundant than in normal cells. Here, we characterised the immune cells of a rare tumor type called small-intestinal neuroendocrine tumors (SINET). We find that so called tumour-infiltrating lymphocytes (TILs) can be grown in the laboratory and activated by challenging them with digested tumor. This study provides insights into the largely unknown SINET immune landscape and reveals the anti-tumour reactivity of TILs, which might merit adoptive T cell transfer as a feasible treatment option for patients with SINET.Traditionally, immune evasion and immunotherapy have been studied in cancers with a high mutational load such as melanoma or lung cancer. In contrast, small intestinal neuroendocrine tumours (SINETs) present a low frequency of somatic mutations and are described as genetically stable tumours, rendering immunotherapies largely unchartered waters for SINET patients. SINETs frequently metastasise to the regional lymph nodes and liver at the time of diagnosis, and no curative treatments are currently available for patients with disseminated disease. Here, we characterised the immune landscape of SINET and demonstrated that tumour-infiltrating lymphocytes (TILs) can be expanded and activated during autologous tumour challenge. The composition of lymphocyte subsets was determined by immunophenotyping of the SINET microenvironment in one hepatic and six lymph node metastases. TILs from these metastases were successfully grown out, enabling immunophenotyping and assessment of PD-1 expression. Expansion of the TILs and exposure to autologous tumour cells in vitro resulted in increased T lymphocyte degranulation. This study provides insights into the largely unknown SINET immune landscape and reveals the anti-tumour reactivity of TILs, which might merit adoptive T cell transfer as a feasible treatment option for patients with SINET.

Highlights

The immune system monitors the body for foreign antigens but can detect cancer cells
Combined with a promotion of an immunosuppressive microenvironment seen in neuroendocrine neoplasms [6] and other tumour types, this results in a poor expansion of antigen-specific T cells and immune evasion
We showed that tumour-infiltrating lymphocytes (TILs) from small intestinal neuroendocrine tumours (SINETs) can be expanded, and the expanded REP-TILs elicit an anti-tumour response when challenged with autologous tumour cells

Summary

Introduction

The immune system monitors the body for foreign antigens but can detect cancer cells. Mutated proteins (neoantigens) or highly overexpressed proteins (tumour-associated antigens) give rise to peptides presented on MHC molecules on, e.g., cancer cells, which can be recognised by antigen-specific T lymphocytes [1]. Cancer cells utilise several immune evasion mechanisms, most notably expression of PD-L1, the ligand of the immune checkpoint PD-1. This is the basis of immune checkpoint inhibitor (ICI) therapy which, along with adoptive T cell therapy (ACT), has demonstrated curative effects in many tumour types [2,3]. Combined with a promotion of an immunosuppressive microenvironment seen in neuroendocrine neoplasms [6] and other tumour types, this results in a poor expansion of antigen-specific T cells and immune evasion

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