Immunophenotype of Gastric Tumors Unveils a Pleiotropic Role of Regulatory T Cells in Tumor Development
by
, , , , , ,
Sara Rocha
1,2,3
,
Afonso P Basto
4,5,
Marieke E Ijsselsteijn
6,
Sara P Teles
1,2,
Maria M Azevedo
1,
Gilza Gonçalves
7,
Irene Gullo
1,2,7,8,
Gabriela M Almeida
1,2,7,
Joaquín J Maqueda
1,2,
Marta I Oliveira
9,
Fátima Carneiro
1,2,7,8,
João T Barata
4, 
Luís Graça
4,5,
Noel F C C de Miranda
6, 
Joana Carvalho
1,2 and
Carla Oliveira
1,2,7,* 1
i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
2
Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
3
Doctoral Program on Cellular and Molecular Biotechnology Applied to Health Sciences, ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
4
iMM—Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisbon, Portugal
5
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal
6
Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
7
Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal
8
Department of Pathology, Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal
9
International Iberian Nanotechnology Laboratory, 4715-330 Braga, Portugal
*
Author to whom correspondence should be addressed.
Cancers 2021, 13(3), 421; https://doi.org/10.3390/cancers13030421
Submission received: 10 December 2020
/
Revised: 19 January 2021
/
Accepted: 20 January 2021
/
Published: 23 January 2021
(This article belongs to the Special Issue CD4 T Cells and Cancer Immune Response)
Simple Summary
The role of regulatory T cells (Tregs) in gastric cancer (GC) is still controversial and poorly understood. GC patients have increased numbers of Tregs in peripheral blood and among tumor infiltrating lymphocytes; however, their prognostic value depends on specific tumor features (e.g., tumor location and/or microsatellite instability status). We found that Tregs might induce membrane expression of IL2Rα in intestinal-type GC cells, which associates with MAPK signaling pathway activation and spheroid growth. Moreover, Tregs accumulate at early steps of intestinal-type GCs progression, when tumors are starting to grow through the stomach wall, and do not present vascular and perineural invasion. Our findings suggest a novel non-immunosuppressive role of Treg cells in intestinal-type GC, which may unlock novel therapeutic immuno-oncology strategies for intestinal-type GC or other tumors with similar immune context.
Abstract
Gastric cancer (GC) patients display increased regulatory T cell (Tregs) numbers in peripheral blood and among tumor-infiltrating lymphocytes. Nevertheless, the role of Tregs in GC progression remains controversial. Here, we sought to explore the impact of Tregs in GCs with distinct histology, and whether Tregs can directly influence tumor cell behavior and GC development. We performed a comprehensive immunophenotyping of 82 human GC cases, through an integrated analysis of multispectral immunofluorescence detection of T cells markers and patient clinicopathological data. Moreover, we developed 3D in vitro co-cultures with Tregs and tumor cells that were followed by high-throughput and light-sheet imaging, and their biological features studied with conventional/imaging flow cytometry and Western blotting. We showed that Tregs located at the tumor nest were frequent in intestinal-type GCs but did not associate with increased levels of effector T cells. Our in vitro results suggested that Tregs preferentially infiltrated intestinal-type GC spheroids, induced the expression of IL2Rα and activation of MAPK signaling pathway in tumor cells, and promoted spheroid growth. Accumulation of Tregs in intestinal-type GCs was increased at early stages of the stomach wall invasion and in the absence of vascular and perineural invasion. In this study, we proposed a non-immunosuppressive mechanism through which Tregs might directly modulate GC cells and thereby promote tumor growth. Our findings hold insightful implications for therapeutic strategies targeting intestinal-type GCs and other tumors with similar immune context.
