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. 2020 Jun 19;9(6):1498.
doi: 10.3390/cells9061498.

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

Irene Gullo  1   2   3   4 , Catarina Costa  1   2 , Susana L Silva  5   6   7 , Cristina Ferreira  5   6   7 , Adriana Motta  5   6 , Sara P Silva  5   6   7 , Rúben Duarte Ferreira  5   6 , Pedro Rosmaninho  5   6 , Emília Faria  8 , José Torres da Costa  9 , Rita Câmara  10 , Gilza Gonçalves  1   3   4 , João Santos-Antunes  11 , Carla Oliveira  2   3   4 , José C Machado  2   3   4 , Fátima Carneiro  1   2   3   4 , Ana E Sousa  5   6
Affiliations

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

Irene Gullo et al. Cells. .

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.

Keywords: Helicobacter pylori; common variable immunodeficiency; gastric cancer; immune dysfunctionality; immune microenvironment; inborn errors of immunity; lymphocytic gastritis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Non-neoplastic gastric mucosa displaying (a) lymphoid follicle with germinal center (Haematoxylin and Eosin, HE, 100×) (c) with CD20+ lymphocytes (IHC, 100×) and absence of CD138+ plasma cells (e) (IHC, 100×)—Patient 9. (b) Non-neoplastic gastric mucosa displaying a lymphoid follicle without germinal center (HE, 100×) with (d) CD20+ lymphocytes and (f) scattered CD138+ plasma cells at the periphery (arrows)—Patient 4.
Figure 2
Figure 2
Morphology of common variable immunodeficiency (CVID)-associated gastric cancer. (a) Tubular gastric cancer, low-grade (HE, 100× magnification); (b) tubular gastric cancer, high-grade (HE, 100× magnification); (c) mucinous adenocarcinoma (HE, 50× magnification); (d) poorly-cohesive carcinoma, PCC-NOS (HE, 200× magnification). Note the presence of scattered signet ring cells (arrows); (e,f) adenomatous lesion, low-grade dysplasia, with tubular (e) and villous (f) architecture (HE, 50× magnification).
Figure 3
Figure 3
(a) Intraepithelial lymphocyte counts in non-neoplastic mucosa distant from gastric cancer in CVID and non-CVID patients; (b) counts of immune cells in the lamina propria in non-neoplastic mucosa distant from gastric cancer in CVID and non-CVID patients. Statistically significant results are highlighted by asterisks: * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001.
Figure 4
Figure 4
(a) Prominent lymphocytic gastritis in non-neoplastic mucosa distant from gastric cancer in a CVID patient (HE, 200×); (b) non-neoplastic mucosa distant from gastric cancer in a non-CVID patient without features of lymphocytic gastritis (HE, 200×); (c,d) non-neoplastic mucosa distant from gastric cancer in a CVID patient (c) showing higher CD8+ lymphocyte count in lamina propria as compared to a non-CVID patient (d) (IHC, 200×); (e,f) non-neoplastic mucosa distant from gastric cancer in a CVID patient (e) showing lower CD20+ lymphocyte count in the intraepithelial compartment as compared to a non-CVID patient (f) (IHC, 200×). Positive cells are highlighted by a red circle.
Figure 5
Figure 5
(a) Intraepithelial lymphocyte counts in non-neoplastic mucosa adjacent to gastric cancer from CVID and non-CVID patients; (b) counts of immune cells in the lamina propria in non-neoplastic mucosa adjacent to gastric cancer from CVID and non-CVID patients. Statistically significant results are highlighted by asterisks: * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001.
Figure 6
Figure 6
Lymphocyte counts in gastric cancer from CVID and non-CVID patients. Statistically significant results are highlighted by asterisks: * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001.
Figure 7
Figure 7
Modifications of lymphocyte counts from non-neoplastic mucosa to gastric cancer in CVID and non-CVID patients analysed separately. ND, non-neoplastic distant from tumour; NA, non-neoplastic adjacent to tumour; GC, gastric cancer. Statistically significant results are highlighted by asterisks: * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001.
Figure 8
Figure 8
Defective immune environment in CVID and putative mechanisms leading to increased susceptibility to gastric cancer.
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