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The relationship between tumour infiltrating lymphocytes, Epstein–Barr virus and Helicobacter pylori infection in gastric cancer

OBJECTIVE: Epstein–Barr virus (EBV) and Helicobacter pylori (HP) infections have been extensively recognised as gastric cancer (GC) triggers, and recent publications suggest they could behave as predictive markers for immune-modulating therapies. Tumour-infiltrating lymphocytes (TILs) have also been...

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Autores principales: Castañeda, Carlos, Castillo, Miluska, Bernabe, Luis, Suarez, Nancy, Fassan, Matteo, Sanchez, Joselyn, Tello, Katherine, Alatrista, Raul, Chavez, Ivan, Ruiz, Eloy, Bazan, Yaqueline, Barreda, Fernando, Valdivia, Daniel, Meng, Wei, Chakravarti, Arnab, Sanchez, Juvenal, Taxa, Luis, Montenegro, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cancer Intelligence 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9085163/
https://www.ncbi.nlm.nih.gov/pubmed/35685959
http://dx.doi.org/10.3332/ecancer.2022.1362
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author Castañeda, Carlos
Castillo, Miluska
Bernabe, Luis
Suarez, Nancy
Fassan, Matteo
Sanchez, Joselyn
Tello, Katherine
Alatrista, Raul
Chavez, Ivan
Ruiz, Eloy
Bazan, Yaqueline
Barreda, Fernando
Valdivia, Daniel
Meng, Wei
Chakravarti, Arnab
Sanchez, Juvenal
Taxa, Luis
Montenegro, Paola
author_facet Castañeda, Carlos
Castillo, Miluska
Bernabe, Luis
Suarez, Nancy
Fassan, Matteo
Sanchez, Joselyn
Tello, Katherine
Alatrista, Raul
Chavez, Ivan
Ruiz, Eloy
Bazan, Yaqueline
Barreda, Fernando
Valdivia, Daniel
Meng, Wei
Chakravarti, Arnab
Sanchez, Juvenal
Taxa, Luis
Montenegro, Paola
author_sort Castañeda, Carlos
collection PubMed
description OBJECTIVE: Epstein–Barr virus (EBV) and Helicobacter pylori (HP) infections have been extensively recognised as gastric cancer (GC) triggers, and recent publications suggest they could behave as predictive markers for immune-modulating therapies. Tumour-infiltrating lymphocytes (TILs) have also been identified as a predictive biomarker for immunotherapy in different malignancies. This study aimed to investigate the association between EBV and HP infection with TIL levels in GC. METHODS: TIL evaluation in haematoxylin-eosin was performed by a pathologist and density of CD3, CD8 and CD163 positive (immunohistochemistry staining) immune cells was calculated with the use of digital pathology software. EBV infection was detected by in situ hybridisation (ISH) and by quantitative polymerase chain reaction (qPCR). Methylation status of EBV-related genes was detected by PCR and a methylome analysis was performed by the Illumina Infinium MethylationEPIC BeadChip. HP status was detected by qPCR. RESULTS: We included 98 resected GC Peruvian cases in our evaluation. Median TIL percentage was 30. The proportion of EBV+ detected by ISH was 24.1%, of EBV+ detected by qPCR was 41.8%, while 70% showed methylation of EBV-related genes, and 58.21% of cases were HP+. Younger age (p = 0.024), early stages (p = 0.001), HP+ (p = 0.036) and low CD8 density (p = 0.046) were associated with longer overall survival (OS). High TIL level was associated with intestinal subtype (p < 0.001), with grade 2 (p < 0.001), with EBV qPCR+ (p = 0.001), and with methylation of EBV-related genes (p = 0.007). Cases with high TIL level and cases that are EBV positive share eight genes with similarly methylated status in the metabolomic analysis. High CD8 density was associated with EBV PCR+ (p = 0.012) and HP− (0.005). CONCLUSION: Lower CD8 density and HP+ predict longer OS. High TIL level is associated with EBV+ and methylation of EBV-related genes, while lower CD8 density is associated with HP+ GC.
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spelling pubmed-90851632022-06-08 The relationship between tumour infiltrating lymphocytes, Epstein–Barr virus and Helicobacter pylori infection in gastric cancer Castañeda, Carlos Castillo, Miluska Bernabe, Luis Suarez, Nancy Fassan, Matteo Sanchez, Joselyn Tello, Katherine Alatrista, Raul Chavez, Ivan Ruiz, Eloy Bazan, Yaqueline Barreda, Fernando Valdivia, Daniel Meng, Wei Chakravarti, Arnab Sanchez, Juvenal Taxa, Luis Montenegro, Paola Ecancermedicalscience Research OBJECTIVE: Epstein–Barr virus (EBV) and Helicobacter pylori (HP) infections have been extensively recognised as gastric cancer (GC) triggers, and recent publications suggest they could behave as predictive markers for immune-modulating therapies. Tumour-infiltrating lymphocytes (TILs) have also been identified as a predictive biomarker for immunotherapy in different malignancies. This study aimed to investigate the association between EBV and HP infection with TIL levels in GC. METHODS: TIL evaluation in haematoxylin-eosin was performed by a pathologist and density of CD3, CD8 and CD163 positive (immunohistochemistry staining) immune cells was calculated with the use of digital pathology software. EBV infection was detected by in situ hybridisation (ISH) and by quantitative polymerase chain reaction (qPCR). Methylation status of EBV-related genes was detected by PCR and a methylome analysis was performed by the Illumina Infinium MethylationEPIC BeadChip. HP status was detected by qPCR. RESULTS: We included 98 resected GC Peruvian cases in our evaluation. Median TIL percentage was 30. The proportion of EBV+ detected by ISH was 24.1%, of EBV+ detected by qPCR was 41.8%, while 70% showed methylation of EBV-related genes, and 58.21% of cases were HP+. Younger age (p = 0.024), early stages (p = 0.001), HP+ (p = 0.036) and low CD8 density (p = 0.046) were associated with longer overall survival (OS). High TIL level was associated with intestinal subtype (p < 0.001), with grade 2 (p < 0.001), with EBV qPCR+ (p = 0.001), and with methylation of EBV-related genes (p = 0.007). Cases with high TIL level and cases that are EBV positive share eight genes with similarly methylated status in the metabolomic analysis. High CD8 density was associated with EBV PCR+ (p = 0.012) and HP− (0.005). CONCLUSION: Lower CD8 density and HP+ predict longer OS. High TIL level is associated with EBV+ and methylation of EBV-related genes, while lower CD8 density is associated with HP+ GC. Cancer Intelligence 2022-03-01 /pmc/articles/PMC9085163/ /pubmed/35685959 http://dx.doi.org/10.3332/ecancer.2022.1362 Text en © the authors; licensee ecancermedicalscience. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0 (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Castañeda, Carlos
Castillo, Miluska
Bernabe, Luis
Suarez, Nancy
Fassan, Matteo
Sanchez, Joselyn
Tello, Katherine
Alatrista, Raul
Chavez, Ivan
Ruiz, Eloy
Bazan, Yaqueline
Barreda, Fernando
Valdivia, Daniel
Meng, Wei
Chakravarti, Arnab
Sanchez, Juvenal
Taxa, Luis
Montenegro, Paola
The relationship between tumour infiltrating lymphocytes, Epstein–Barr virus and Helicobacter pylori infection in gastric cancer
title The relationship between tumour infiltrating lymphocytes, Epstein–Barr virus and Helicobacter pylori infection in gastric cancer
title_full The relationship between tumour infiltrating lymphocytes, Epstein–Barr virus and Helicobacter pylori infection in gastric cancer
title_fullStr The relationship between tumour infiltrating lymphocytes, Epstein–Barr virus and Helicobacter pylori infection in gastric cancer
title_full_unstemmed The relationship between tumour infiltrating lymphocytes, Epstein–Barr virus and Helicobacter pylori infection in gastric cancer
title_short The relationship between tumour infiltrating lymphocytes, Epstein–Barr virus and Helicobacter pylori infection in gastric cancer
title_sort relationship between tumour infiltrating lymphocytes, epstein–barr virus and helicobacter pylori infection in gastric cancer
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9085163/
https://www.ncbi.nlm.nih.gov/pubmed/35685959
http://dx.doi.org/10.3332/ecancer.2022.1362
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