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IMMUNOPROFILING OF T CELL SUBTYPES IN EARLY-ONSET VERSUS LATER-ONSET COLORECTAL TUMORS: INSIGHTS FROM ENDOSCOPICALLY RESECTED SPECIMENS

Naohiko Akimoto 1, Atsushi Tatsuguchi 1, AITOSHI HOSHIMOTO 1, Shun Nakagome 1, Yuka Shimazu 1, Ryosuke Inoue 1, Tsugumi Habu 1, Eriko Koizumi 1, Kazutoshi Higuchi 1, Takayoshi Nishimoto 1, Jun Omori 1, Ryuji Ohashi 1, Masanori Atsukawa 1

Affiliations

1 Nippon Medical School, Graduate School of Medicine, Tokyo, Japan

Summary

AI Generated

Analysis of 306 colorectal lesions from Japan shows that early-onset tumors (diagnosed before age 50) have significantly lower densities of CD3+, CD4+, and CD8+ T cells compared with later-onset tumors, with T cell densities also varying by tumor size and location.

Early-onset colorectal tumors had significantly lower numbers of CD3+, CD4+, and CD8+ T cells compared with later-onset tumors (all P less than 0.001), while FOXP3+ T cell numbers showed no significant difference between groups
The densities of CD3+, CD4+, and CD8+ T cells decreased with increasing tumor diameter (all P less than 0.001)
The distributions of CD3+, CD8+, and FOXP3+ T cells differed significantly by tumor location in the proximal colon, distal colon, or rectum
The study analyzed 214 early-onset lesions among 306 total colorectal lesions resected endoscopically at a single Japanese hospital between February 2017 and January 2020
The authors suggest these findings highlight the need for further research to identify early-onset colorectal tumor subsets that may require more intensive surveillance based on immunological profiles

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Abstract

Introduction

The global incidence of early-onset colorectal cancer is rising at an alarming rate, underscoring the urgent need for effective preventive and therapeutic strategies. While age-associated molecular and pathological alterations have been reported, the immunological landscape—particularly the roles of distinct T cell subtypes in anti-tumor immunity—remains poorly characterized in early-onset colorectal tumor, especially in endoscopically resected colorectal tumors.
In this study, we investigated the association between T cell subtype densities—specifically CD3+, CD4+, CD8+, and FOXP3+ T cells—and clinicopathological features, with a particular focus on tumors arising in younger individuals. Early-onset colorectal tumors were defined as those diagnosed before the age of 50, whereas later-onset tumors were defined as those diagnosed at age 50 or older.

Aims & Methods

This study aimed to evaluate the relationship between T cell subtypes and the clinicopathological features of early-onset colorectal tumors. We utilized a molecular pathology database comprising 169 cases of colorectal cancer and adenoma, analyzing a total of 306 colorectal lesions. Among these, 214 lesions were classified as early-onset tumors and had been resected via endoscopic techniques—including cold snare polypectomy, endoscopic mucosal resection, and endoscopic submucosal dissection—at Nippon Medical School Hospital in Japan between February 2017 and January 2020.
Formalin-fixed paraffin-embedded (FFPE) tissue blocks were collected, and immunohistochemical staining for CD3, CD4, CD8, and FOXP3 was conducted. The densities of CD3+, CD4+, CD8+, and FOXP3+ cells were quantified within tumor, stromal, and normal tissue regions. Depending on lesion size, one to five fields of view (median: five) were selected and imaged at 200x magnification using a BZX800 fluorescence microscope (KEYENCE). Automated image analysis was employed to determine the average number of each T cell subtype. Quantification within stromal and normal regions was restricted to specimens with sufficiently large resected tissue to include these areas in addition to tumor tissue. Clinicopathological variables were assessed retrospectively. Statistical analyses included the chi-square test for categorical variables, Spearman’s rank correlation for assessing associations, the Mann–Whitney U test for comparison of continuous variables, and the Kruskal–Wallis test for comparisons across three or more groups.

Results

Tumor locations were distributed as follows: 126 cases (41%) in the proximal colon, 142 cases (47%) in the distal colon, and 37 cases (12%) in the rectum. Compared with later-onset colorectal tumors, early-onset tumors had significantly lower numbers of CD3+, CD4+, and CD8+ T cells (all P <0.001). In contrast, no significant difference was observed in the number of FOXP3+ T cells between the two groups.
Additionally, the densities of CD3+, CD4+, and CD8+ T cells decreased with increasing tumor diameter (all P <0.001). The distributions of CD3+, CD8+, and FOXP3+ T cells also differed significantly by tumor location (P = 0.040, 0.006, and 0.013, respectively).

Conclusion

Analysis of endoscopically resected specimens suggests that anti-tumor immune responses mediated by T cells may vary depending on age of onset, tumor size, and tumor location. These findings highlight the need for further research to identify subsets of early-onset colorectal tumors that may require more intensive surveillance following endoscopic resection, based on their immunological profiles.

Conference

UEG Week Berlin 2025

Topics

Colorectal

Submission format

Abstract

Session

Unveiling colorectal cancer (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Unraveling Steatotic Liver Diseases: Insights from Amino Acid and TCA Cycle Metabolomics

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Unraveling Steatotic Liver Diseases: Insights from Amino Acid and TCA Cycle Metabolomics

Masaaki Mino 1

Affiliations

1 Kohnodai Hospital, National Center for Global Health and Medicine, Kōnodai, Japan

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Abstract

Event

UEG Week Berlin 2025

Topics

Hepatobiliary

Session

Rising Stars from Europe and Japan: Metabolic liver diseases

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Time management: How can we save time?

Deepa Jegadish Gandhi 1

Affiliations

1 Mater Misericordiae University Hospital, Dublin, Ireland

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Abstract

Event

UEG Week Berlin 2025

Topics

Nurses

Session

Staff safety and management

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Laudatio UEG Lifetime Achievement Awardee

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Laudatio UEG Lifetime Achievement Awardee

Mario Dinis-Ribeiro 1

Affiliations

1 IPO Porto, Porto, Portugal

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Abstract

Event

UEG Week Berlin 2025

Topics

Immunology

Session

Opening Plenary

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Ute Pfeifer 1

Affiliations

1 Evangel. Krankenhaus Düsseldorf Abt. Endoskopie, Düsseldorf, Germany

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Abstract

Event

UEG Week Berlin 2025

Topics

Nurses

Session

Staff safety and management

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Laudatio UEG Lifetime Achievement Awardee

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József Maléth

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Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

STORE-INDEPENDENT ORAI1 SIGNALING DEFINES BASAL CFTR FUNCTION IN SECRETORY EPITHELIA

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

Not sure what you can access? Learn more about account types.

STORE-INDEPENDENT ORAI1 SIGNALING DEFINES BASAL CFTR FUNCTION IN SECRETORY EPITHELIA

Aletta Kata Kiss 1, Arpad Varga 1, Marietta Görög 2, Tamara Madacsy 1, Woo Young Chung 3, Petra Pallagi 1, Viktória Szabó 1, Petra Susánszki 2, Enikő Kúthy-Sutus 1, Szintia Barnai 2, Dániel Varga 4, Péter Bíró 4, Ingrid Hegnes Sendstad 1, Tim Crul 1, Boldizsár Jójárt 1, Bálint Tél 5, Anita Balazs 6, György Lázár 4, Miklós Erdélyi 4, Shmuel Muallem 3, József Maléth 1

Affiliations

1 University of Szeged, Szeged, Hungary|||University of Szeged, Szeged, Hungary|||University of Szeged, Szeged, Hungary

2 University of Szeged, Szeged, Hungary|||University of Szeged, Szeged, Hungary

3 National Institutes of Health, Bethesda, United States

4 University of Szeged, Szeged, Hungary

5 University of Szeged, Szeged, Hungary|||University of Szeged, Szeged, Hungary|||Semmelweis University, Budapest, Hungary

6 Charité Universitätsmedizin Berlin, Berlin, Germany

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Abstract

Introduction

Cystic fibrosis transmembrane conductance regulator (CFTR) is essential for epithelial ion and fluid secretion. While CFTR is primarily activated via cAMP/PKA signaling, the role of intracellular Ca²⁺ signaling—particularly through store-independent mechanisms—remains incompletely understood.

Aims & Methods

We aimed to elucidate how store-independent Ca²⁺ influx via Orai1 regulates basal CFTR activity in primary polarized epithelial cells.
To investigate this we used mouse and human pancreatic, hepatic and airway organoids, we combined RNA-sequencing, immunofluorescence, Fura-2 and MQAE dye-based Ca²⁺/Cl⁻ imaging, FLIM-FRET, dSTORM microscopy, and in vivo fluid secretion assays. Genetic silencing and pharmacological inhibition (CM5480) were employed to dissect Orai1-dependent signaling pathways.

Results

We discovered that Orai1 mediates a constitutive, store-independent Ca²⁺ influx sustained by SPCA2. This influx occurs independently of ER Ca²⁺ depletion but requires STIM1. Super-resolution imaging revealed Orai1 clustering into discrete apical membrane nanodomains that colocalize with SPCA2, STIM1, PKA, and CFTR. Functional assays confirmed that this localized signaling complex maintains basal CFTR activity. Inhibiting Orai1 reduced basal Cl⁻ and HCO₃⁻ secretion, disrupted mitochondrial ATP production, and suppressed pancreatic ductal fluid secretion in vitro and in vivo. Further, the stimulatory effect of this Ca²⁺ influx on CFTR was mediated via Ca²⁺/calmodulin-sensitive adenylyl cyclases (AC1, 3, 8), which were co-clustered with Orai1 and CFTR. Their knockdown phenocopied Orai1 inhibition, and no additive effect was observed when both pathways were blocked.

Conclusion

Our results reveal a previously unrecognized SPCA2–STIM1–Orai1 nanodomain that drives store-independent Ca²⁺ influx, activating CFTR via local cAMP production in the absence of neurohormonal stimuli. This regulatory module is conserved across secretory epithelia and represents a key mechanism for maintaining basal fluid secretion and epithelial homeostasis.

Event

UEG Week Berlin 2025

Topics

Mechanisms & Personalised Medicine Pancreas

Submission format

Abstract

Session

Cogulation, lipids and bugs: All relevant for pancreatitis

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Unraveling Steatotic Liver Diseases: Insights from Amino Acid and TCA Cycle Metabolomics

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Mario Dinis-Ribeiro

European survey on physical and mental health in endoscopy

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József Maléth

Accreditation for a newly recruited endoscopy nurse

Anne Vidil

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

Accreditation for a newly recruited endoscopy nurse

This content is part of Gutflix. Log in with your myUEG account, or create one free, to watch it.

Not sure what you can access? Learn more about account types.

Accreditation for a newly recruited endoscopy nurse

Anne Vidil 1

Affiliations

1 None, None, France

Summary

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Abstract

Event

UEG Week Berlin 2025

Topics

Nurses

Session

Education: Important tool for quality in endoscopy

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

Unraveling Steatotic Liver Diseases: Insights from Amino Acid and TCA Cycle Metabolomics

Masaaki Mino

Time management: How can we save time?

Deepa Jegadish Gandhi

Laudatio UEG Lifetime Achievement Awardee

Mario Dinis-Ribeiro

European survey on physical and mental health in endoscopy

Ute Pfeifer

STORE-INDEPENDENT ORAI1 SIGNALING DEFINES BASAL CFTR FUNCTION IN SECRETORY EPITHELIA

József Maléth

Accreditation for a newly recruited endoscopy nurse

Anne Vidil

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