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KRAS-M6A EPITRANSCRIPTOME AXIS PROMOTES CD4+ T-CELL-MEDIATED IMMUNOSUPPRESSION IN COLORECTAL CANCER

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Introduction

Most colorectal cancer (CRC) patients are nonresponsive to immune checkpoint blockade (ICB) therapy. KRAS is a key oncogenic factor in CRC, and it has been reported that mutant KRAS blunts ICB therapy efficacy. Thus, there is a need to unravel immunotherapeutic targets for KRAS-mutant CRC. In this study, we demonstrated that mutant KRAS-driven m⁶A epitranscriptome underlies immunosuppression in CRC through the regulation of CD4⁺ T cells in the tumor immune microenvironment.

Aims & Methods

M⁶A modification in KRAS-mutant CRC cells, transgenic Apc^Min/+Kras^G12D/+ mice, and human CRC patients were determined by dot blot and LC-MS. Mutant KRAS-driven m⁶A epitranscriptome was characterized by integrative m⁶A sequencing, RNA sequencing, RNA co-immunoprecipitation sequencing and ribosome-sequencing. The immune landscape in Apc^Min/+ and Apc^Min/+Kras^G12D/+ mice was profiling by mass cytometry-time of flight analysis and flow cytometry. Effect of KRAS-m6A axis on antitumor immunity was investigated by knockout of target genes and in vivo validation.

Results

Analysis of isogenic CRC cell lines harbouring wildtype and mutant KRAS showed that mutant KRAS dramatically global m⁶A RNA modification, and overall m⁶A level was also increased in transgenic Apc^Min/+Kras^G12D/+ mice. Consistent with this, mutant KRAS strongly elevated protein expression of METTL3, a m⁶A writer, as well as YTHDF1, a m⁶A reader, in CRC cells and mouse models, an effect mediated by suppressing their protein degradation via autophagic pathway. To decipher the consequence of KRAS-induced m⁶A, integrated m⁶A-seq, RNA-immunoprecipitation-seq and RNA-seq were performed, identifying BCL9L as a unique gene with concomitant upregulation of METTL3-driven m⁶A and mRNA expression in KRAS-mutant CRC, and is targeted by YTHDF1 for translation. The co-operative interplay between METTL3 and YTHDF1 led to increased expression of BCL9L in KRAS-mutant CRC cells and in Apc^Min/+Kras^G12D/+ mice. Functional investigation demonstrated that BCL9L did not exert a proliferative effect; instead, it was closely correlated with cytokine-cytokine receptor pathway. Indeed, BCL9L silencing downregulated secretion of immunosuppressive cytokines TGFβ1-3, LIF, and TIMP1, implying that m⁶A-BCL9L axis might be involved in immunosuppression in KRAS-mutant CRC. We hence performed multi-parameter immune cell phenotyping by mass cytometry in Apc^Min/+ and Apc^Min/+Kras^G12D/+ mice, mutant KRAS markedly depleted CD4⁺ T cells whilst promoting the accumulation of CD4⁺ T_reg cells. On the other hand, the knockout of BCL9L reversed the effect of mutant KRAS in vivo by reactivation of CD4⁺ T cells and their TNF-α and IFN-γ expression, together with the suppression of CD4⁺ T_reg cells, inferring the role of BCL9L in mutant KRAS-mediated immunosuppression. Finally, we demonstrated that BCL9L mRNA and protein expression as novel prognostic factors that predict poor survival in KRAS-mutant CRC, but not KRAS-wildtype CRC patients.

Conclusion

We identified a mutant KRAS-m⁶A axis in CRC leading to increased expression of BCL9L, which in turn drives an immunosuppressive tumor microenvironment by regulating CD4⁺ T cells and CD4⁺ T_reg cells. BCL9L is a potential therapeutic target and prognostic marker for KRAS-mutant CRC.

References

No.

KRAS-M6A EPITRANSCRIPTOME AXIS PROMOTES CD4+ T-CELL-MEDIATED IMMUNOSUPPRESSION IN COLORECTAL CANCER

Danyu CHEN 1, Lianxin ZHOU 1, Jun Yu 1, Chi Chun Wong 2

1 The Chinese University of Hong Kong, Hong Kong, Hong Kong

2 Medicine and Therapeutics, Shatin, Hong Kong

Event

UEG Week Copenhagen 2023

Topics

Colorectal Digestive Oncology Hepatobiliary Mechanisms & Personalised Medicine Pancreas

Submission format

Abstract

Session

Carcinogenesis revisited

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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JAK2 INHIBITION ATTENUATES PORTAL HYPERTENSION IN METABOLIC DYSFUNCTION-ASSOCIATED LIVER

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Introduction

Portal hypertension (PHT) most commonly due to cirrhosis, but non-cirrhotic portal hypertension (NCPH) related to metabolic dysfunction, specifically metabolic dysfunction-associated steatotic liver disease (MASLD), necessitates further clarification of its mechanisms and identification of therapeutic targets.

PHT may precede the development of hepatic fibrosis in MASLD, and even serve as a driving factor in the pathogenesis of MASLD. Consequently, metabolic dysfunction-associated PHT might not depend on structural alterations such as hepatic fibrosis or pseudolobule formation, but rather correlate with other factors such as endothelial dysfunction, which has been demonstrated to play a pivotal role in NCPH. Endothelial dysfunction encompasses endothelial injury and endothelial-to-mesenchymal transition (EndMT), the latter being a specific type of epithelial-to-mesenchymal transition (EMT). As reported, the JAK/STAT3 signaling pathway plays a pivotal role in the initiation and progression of EMT. Similarly, patients with NCPH induced by myeloproliferative neoplasms (MPN) often lack pathological features such as hepatic fibrosis or pseudolobule formation. The Janus kinase 2 (JAK2) V617F mutation is highly prevalent in MPN patients. Therefore, targeted inhibition of JAK2 serves as an effective therapeutic strategy for MPN.

Given the shared pathological features between MPN-associated portal hypertension and MASLD-associated portal hypertension, as well as the vital role of JAK2 in both disease, the application of JAK2 inhibitor holds significant therapeutic potential for metabolic dysfunction-associated portal hypertension.

Aims & Methods

This study aims to verify the therapeutic efficacy of JAK2 inhibition in attenuating MASLD-associated PHT, with particular focus on its modulation of EndMT. Mice were fed with a high-fat diet (HFD) diet for 12 weeks to induce MASLD-associated PHT and divided into two groups, the treatment group (Rux) and control (Ctr) group. Ruxolitinib (JAK2 inhibitor) was given as a suspension by gavage (60 mg/kg in 0.2 ml) every two days for 3 weeks, while controls received the same volume of saline, from week 10-12 of feeding. Portal pressure was measured, serological analysis and histopathological staining were performed. RT-PCR and Western Blot were conducted to measure EndMT-related genes expression.

Results

The treatment group (Rux) demonstrated a significant reduction in directly measured portal pressure, with concordant changes observed in the spleen-to-body weight ratio, which served as an indirect indicator of portal pressure. Concurrent improvement was noted in ALT, AST and TC. H&E, Masson and Sirius red staining showed decreased perisinusoidal and perivascular fibrosis in the Rux group. Electron microscopy revealed restoration of endothelial fenestration. Additionally, ruxolitinib treatment led to downregulation of endothelial damage markers, mesenchymal cell markers as well as EndMT-related regulatory factors, indicating an alleviation of EndMT and endothelial dysfunction.

Conclusion

The JAK2 inhibitor demonstrates therapeutic potential for MASLD-associated PHT through modulation of endothelial dysfunction and EndMT. These mechanistic insights position ruxolitinib as a promising candidate for clinical management of NCPH, particularly in the MASLD-associated PHT.

References

[1] European Association for the Study of the Liver; European Association for the Study of Diabetes; European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD): Executive Summary. Diabetologia. 2024 Jun 13. [2] Song Z, Liu X, Zhang W, et al. Ruxolitinib suppresses liver fibrosis progression and accelerates fibrosis reversal via selectively targeting Janus kinase 1/2. Journal of Translational Medicine. 2022, 20(1): 157.
[3] Zhang XL, Zhang XY, Ge XQ, et al. Mangiferin prevents hepatocyte epithelial-mesenchymal transition in liver fibrosis via targeting HSP27-mediated JAK2/STAT3 and TGF-β1/Smad pathway. Phytotherapy Research. 2022, 36(11): 4167-4182.
[4] Jin W. Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial-Mesenchymal Transition. Cells. 2020;9(1):217.
[5] Hammoutene A, Rautou PE. Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. Journal of Hepatology. 2019, 70(6): 1278–1291.

JAK2 INHIBITION ATTENUATES PORTAL HYPERTENSION IN METABOLIC DYSFUNCTION-ASSOCIATED LIVER

Yifei Liu 1, Shiyao Chen 1

1 Zhongshan Hospital, Fudan University, Shanghai, China

Event

UEG Week Berlin 2025

Topics

Gut Microbiota Hepatobiliary Mechanisms & Personalised Medicine

Submission format

Abstract

Session

MASLD: Inflammatory mechanisms

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Introduction

Prompt initiation of advanced therapy (AT) medications, encompassing biologics and small molecule treatments, is crucial for the effective treatment of inflammatory bowel disease (IBD). The time taken from the decision to start the AT to it’s first administration, or time to advanced therapy (TAT), can vary significantly between individuals negatively impacting upon their disease course. However, our knowledge of the causes for the variation in TAT is poor.

Aims & Methods

We aimed to investigate the impact that different demographic and disease-related factors have on the TAT. A retrospective analysis of electronic patient records, conducted at a tertiary IBD referral centre in London in March 2024, analysed electronic patient records of all those over the age of 18 currently being treated for IBD with an AT and collected data on the TAT for their index AT, defined as the number of days from the documented decision to start an AT to the date of the first administration. Data was also collected on multiple variables which including disease type, type of AT, age, sex, ethnicity and socioeconomic status by analysing patients’ Index of Multiple Deprivation (IMD). A multiple negative binomial regression was performed entering all variables together to assess their relative effect on TAT.

Results

1298 patients were identified and 485 were excluded due to either their index AT being started elsewhere, incomplete data, a positive screening test or because they were enrolled in a clinical trial. The multiple binomial regression found that TAT was significantly longer for those of non-white ethnicity (p=0.039) (table 1). Analysis for patients of black ethnicity found an Incident Rate Ratio (IRR) of 1.46 (95% CI 1.09,1.95), for mixed ethnicity IRR=1.26 (95% CI 0.77,2.05) and for asian ethnicity IRR=1.17 (95% CI 0.96, 1.41) when compared to white patients. Treatment with adalimumab was also associated with a longer TAT (p=<0.001, IRR 1.37, 95% CI 0.95,1.96) but no other factors were statistically significant: IMD p=0.133; age p=0.155; sex p=0.702; disease type p=0.335.

		IRR	95% CI	p-value
Ethnicity	Asian	1.17	0.96, 1.21	0.039
	Black	1.46	1.09, 1.95
	Mixed	1.26	0.77, 2.05
	White	1
Treatment	Adalimumab	1.37	0.95, 1.96	<0.001
	Filgotinib	1.37	0.87, 2.16
	Infliximab	0.97	0.68, 1.40
	Tofacitinib	0.89	0.58, 1.36
	Ustekinumab	0.91	0.61, 1.35

IRR: Incidence Rate Ratio. IMD: Index of multiple deprivation.

Conclusion

Our study has identified that non-white ethnicity is associated with a longer TAT and this may be a contributing factor to worse outcomes in patients with IBD from an ethnic minority background. Further research into the causes for this are required to help address this health disparity.

DELAYS IN INITIATING ADVANCED THERAPY FOR INFLAMMATORY BOWEL DISEASE: THE IMPACT OF ETHNICITY

Michael Colwill 1, Samantha Baillie 1, Chandni Radia 2, Sarah White 3, Richard Pollok 1, Andrew Poullis 1

1 City St George's, Unviersity of London, London, United Kingdom|||St Georges University Hospitals NHS Foundation Trust, London, United Kingdom

2 King's College Hospital NHS Foundation Trust, London, United Kingdom

3 City St George's, Unviersity of London, London, United Kingdom

Conference

UEG Week Berlin 2025

Topics

IBD

Submission format

Abstract

Session

IBD (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Introduction

Modern lifestyles have increased the demand for convenience and extended shelf life, contributing to the rising consumption of ultra-processed foods (UPFs). This trend has been linked to adverse health outcomes, including obesity and inflammatory bowel disease (IBD). IBD encompasses multifactorial digestive disorders characterized by disrupted intestinal homeostasis, resulting in immune dysregulation, impaired nutrient absorption, systemic inflammation, and a marked reduction in quality of life, often associated with chronic fatigue and decreased physical activity. These factors contribute to the activation of muscle protein catabolism and inhibition of skeletal muscle protein synthesis, increasing the risk of sarcopenia in IBD patients.

Aims & Methods

To evaluate ultra-processed food consumption and body composition in patients with IBD. A cross-sectional study was conducted with 105 patients diagnosed with Crohn’s disease or ulcerative colitis at the IBD outpatient clinic of Hospital das Clínicas, Botucatu Medical School (HC-FMB). Assessments included handgrip strength using a dynamometer, bioelectrical impedance analysis, anthropometric measurements, and dietary intake evaluation using a food frequency questionnaire (FFQ).

Results

The sample included 61 patients with ulcerative colitis and 44 with Crohn’s disease, with a mean age of 41.5 ± 15.1 years; 70% were female. Mean disease duration was 11.2 ± 7.6 years. The average BMI was 25.9 ± 5.2 kg/m², with 52.4% classified as overweight. Mean body fat percentage assessed by skinfold measurements was 28.5 ± 7.5%, with 85% exceeding the reference values. Additionally, 18.3% were classified as malnourished based on mid-arm muscle circumference. According to bioelectrical impedance, 86.4% had low muscle mass. Mean handgrip strength was 27.4 ± 8.7 kgf, with 7% presenting inadequate values. Dietary data showed that 22% reported weekly fast food consumption, 30.5% consumed sweets, and 13% drank artificial juices daily. Daily intake of fruits and vegetables was reported by 48% of participants, and 36% reported daily meat consumption.

Conclusion

Patients with IBD are at increased risk of sarcopenia due to inflammatory burden and dietary restrictions. This study identified reduced muscle mass and high intake of certain processed and ultra-processed foods. Regular consumption of UPFs may worsen disease outcomes and negatively affect body composition by increasing fat mass and decreasing muscle mass. Further analyses will explore associations between UPF intake and changes in body composition.

References

Narula N, Wong ECL, Dehghan M, et al. Association of ultra-processed food intake with risk of inflammatory bowel disease: prospective cohort study. BMJ. 2021;374:n1554.
Racine A, Carbonnel F, Chan SS, et al. Dietary Patterns and Risk of Inflammatory Bowel Disease in Europe: Results from the EPIC Study. Inflamm Bowel Dis 2016;22:345-54. 10.1097/MIB.0000000000000638
SUGIHARA, Kohei; KAMADA, Nobuhiko. Diet–microbiota interactions in inflammatory bowel disease. Nutrients, v. 13, n. 5, p. 1533, 2021.
WANG, Yun et al. Encyclopedia of fecal microbiota transplantation: a review of effectiveness in the treatment of 85 diseases. Chinese Medical Journal, v. 135, n. 16, p. 1927-1939, 2022.
Whelan K, Bancil AS, Lindsay JO, Chassaing B. Ultra-processed foods and food additives in gut health and disease. Nat Rev Gastroenterol Hepatol. 2024;21(6):406-27.
World Health Organization (WHO). Prevalence of obesity among adults, BMI (crude estimate). Disponível em: https://www.who.int/data/gho/data/indicators/indicator-details/GHO/prevalence-of-obesity-among-adults-bmi--30-(crude-estimate). Acesso em 28 dez. 2024.
Meyer A, Dong C, Casagrande C, Chan SSM, Huybrechts I, et al. Food Processing and Risk of Crohn's Disease and Ulcerative Colitis: A European Prospective Cohort Study. Clin Gastroenterol Hepatol. 2023 Jun;21(6):1607-1616.e6.

ULTRA-PROCESSED FOOD CONSUMPTION IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE

Amanda Spiller 1, Beatriz Gabriela Costa 1, Ryan Nunes Yoshio Yoshihara 1, Enya Zucari Nogueira 2, Natália Salvador Castelhano 1, Giedre Soares Prates Herreira 1, Daniela Salate Biagioni Vulcano 1, Lígia Yukie Sassaki 1

1 São Paulo State University (Unesp), Botucatu, Brazil

2 São Paulo State University, Botucatu, Brazil

Conference

UEG Week Berlin 2025

Topics

Small Intestine & Nutrition

Submission format

Abstract

Session

NUTRITION (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Inﬂammation in Crohn’s Disease: The Evolution Continues (Eli Lilly and Company) (Complete Session)

Aline Charabaty 1, James O. Lindsay 2, Joana Torres 3

1 Associate Clinical Professor of Medicine, Johns Hopkins School of Medicine Clinical Director of the IBD Center, Johns Hopkins Sibley Memorial Hospital, Washington, D.C., USA, Washington, D.C., United States of America

2 Digestive Disorders Clinical Academic Unit, BARTS & THE LONDON SCHOOL OF MEDICINE, London, United Kingdom

3 Hospital Beatriz Ângelo, Lisbon, Portugal