The Dysfunctional Immune System in Common Variable Immunodeficiency Increases the Susceptibility to Gastric Cancer.

Irene Gullo,Gilza Gonçalves,Pedro Rosmaninho,Catarina Costa,Emília Faria,Ana E Sousa,João Santos-Antunes,José C Machado,Susana L Silva,Carla Oliveira,Adriana Motta,Cristina Ferreira,José Torres Da Costa,Rúben Duarte Ferreira,Rita Câmara,Sara P Silva,Fátima Carneiro

doi:10.3390/cells9061498

Abstract

Gastric carcinoma (GC) represents the most common cause of death in patients with common variable immunodeficiency (CVID). However, a limited number of cases have been characterised so far. In this study, we analysed the clinical features, bacterial/viral infections, detailed morphology and immune microenvironment of nine CVID patients with GC. The study of the immune microenvironment included automated digital counts of CD20+, CD4+, CD8+, FOXP3+, GATA3+ and CD138+ immune cells, as well as the evaluation of PD-L1 expression. Twenty-one GCs from non-CVID patients were used as a control group. GC in CVID patients was diagnosed mostly at early-stage (n = 6/9; 66.7%) and at younger age (median-age: 43y), when compared to non-CVID patients (p < 0.001). GC pathogenesis was closely related to Helicobacter pylori infection (n = 8/9; 88.9%), but not to Epstein-Barr virus (0.0%) or cytomegalovirus infection (0.0%). Non-neoplastic mucosa (non-NM) in CVID-patients displayed prominent lymphocytic gastritis (100%) and a dysfunctional immune microenvironment, characterised by higher rates of CD4+/CD8+/Foxp3+/GATA3+/PD-L1+ immune cells and the expected paucity of CD20+ B-lymphocytes and CD138+ plasma cells, when compared to non-CVID patients (p < 0.05). Changes in the immune microenvironment between non-NM and GC were not equivalent in CVID and non-CVID patients, reflecting the relevance of immune dysfunction for gastric carcinogenesis and GC progression in the CVID population.

Highlights

Inborn errors of immunity comprise an expanding group of more than 400 diseases which have provided a remarkable unexplored context for research [1]
Nine gastric adenocarcinomas from formalin fixed paraffin-embedded (FFPE) gastric cancer samples of common variable immunodeficiency (CVID) patients, including biopsies (n = 2) and surgical specimens (n = 7), were obtained from a cohort of CVID patients under follow-up at Centro de Imunodeficiências Primárias (CIDP) of Centro Académico de Medicina de Lisboa (Lisbon, Portugal) (n = 6) and from other hospitals belonging to the national network of CIDP (n = 3)
Six of the nine CVID patients belong to a cohort of CVID patients previously described [28] and were diagnosed during a thorough follow-up at CIDP (Lisbon, Portugal), which includes a regular esophagogastroduodenoscopy surveillance protocol [22]

Summary

Introduction

Inborn errors of immunity comprise an expanding group of more than 400 diseases which have provided a remarkable unexplored context for research [1]. Common variable immunodeficiency (CVID) is the most common clinically relevant primary immunodeficiency [2]. It is defined by defects in B-cell differentiation into memory B cells and Ig-secreting plasma cells [2,3,4], though phenotypic and functional abnormalities have been increasingly recognised in T cells [5,6] and innate immunity [7,8]. In addition to recurrent infections primarily in the respiratory and gastrointestinal tracts, the most typical presentation in CVID, clinical manifestations related to immune dysregulation in these patients include autoimmune disorders, a variable spectrum of lymphoproliferative diseases and malignancies [11,12]

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