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ROLE OF CMTM4 IN HELICOBACTER PYLORI INDUCED GASTRIC CANCER

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Introduction

The Helicobacter pylori (H.pylori) infection induced inflammatory response is important to the gastric cancer. IL-17 pathway plays an essential role in the inflammatory response to the H.pylori infection and affects the outcome of the H.pylori related disease. H. pylori infection leads to an increase of IL-17RC protein in both H. pylori treated AGS cells and mice, and IL-17RC is also upregulated in human gastric cancer tissues. Moreover, IL-17A could promote gastric carcinogenesis partly by regulating IL-17RC/NF-κB/NOX1 pathway. The transmembrane protein CMTM4, a recently reported key component of the IL-17 receptor, is required for membrane expression of IL-17 receptor subunit C and activation of IL-17A pro-inflammatory signaling. Until now, the involvement of CMTM4 in the pathogenesis of H.pylori has not yet been reported.

Aims & Methods

The role of CMTM4 both in stabilizing IL-17RC during H.pylori infection and in H.pylori induced gastric disease were analyzed. The in vitro H.pylori-gastric epithelial cell coculture system and in vivo H.pylori infected C57BL/6 mice model were established. The H.pyloricocultured gastric epithelial cells were transfected with a siRNA of CMTM4. Gastric disease model was induced by H.pylori in wild-type (WT) or Cmtm4^-/-(KO) mice and examined at 3 months, 12 months and 22 months post infection. The protein level of IL-17RC after inhibiting CMTM4 was detected both in the H.pylori-gastric epithelial cells and mice gastric mucosa by Western blot and immunohistochemistry (IHC). Hematoxylin-eosin（HE）staining and IHC were used to check the disease symptoms change in Cmtm4 knockout mice. RNA-sequencing（RNA-seq）was done to clarify the mechanism of delayed gastric cancer development in the Cmtm4 knockout group.

Results

Both the H.pylori treated gastric epithelial cells and mice gastric mucosa showed decreased IL-17RC protein expression in the CMTM4 deficiency group. HE staining results showed the H.pylori infected mice appeared spasmolytic polypeptide expressing metaplasia (SPEM) like symptoms at 12 months after H.pylori infection and the tumor developed mostly in the pyloric mucosa adjacent to the fundic region at 22 months post infection. Histopathologically, the overall incidence of stomach tumors was lower in the Cmtm4 deficient group. In addition to tumor classification, the pre-cancerous lesions, such as inflammation, foveolar hyperplasia, intestinal metaplasia, SPEM, and dysplasia, were also investigated. These lesions still milder in Cmtm4 KO mice. Moreover, the Cmtm4 deficient mice exhibited lower number of Ly6G-positive cells infiltration than WT mice at 3 months post infection. That indicates Cmtm4 depletion inhibits the progression of multistep carcinogenesis of gastric cancer. Furthermore, the RNA-seq analysis of the gastric mucosa showed down-regulated IL-17 signaling pathway, including decreased chemokines Cxcl2, Ccl20, cytokine Tnf and matrix metalloproteinase (MMP) Mmp9. The in vitro H.pylori-gastric epithelial cell coculture results also exhibited lower expression of Ccl20, Mmp2, and antimicrobial peptides S100a7 in the CMTM4 deficiency group.

Conclusion

Cmtm4 deficiency down-regulated the protein level of IL-17RC in the H.pylori infected gastric epithelial cells and mice gastric mucosa. Loss of Cmtm4 inhibited the gastric cancer development through the IL-17 signaling pathway.

References

1. Shiomi S, Toriie A, Imamura S, et al. IL-17 is involved in Helicobacter pylori-induced gastric inflammatory responses in a mouse model. Helicobacter 2008; 13(6): 518-24.
2. Kang JH, Park S, Rho J, et al. IL-17A promotes Helicobacter pylori-induced gastric carcinogenesis via interactions with IL-17RC. Gastric Cancer 2023; 26(1): 82-94.
3. Knizkova D, Pribikova M, Draberova H, et al. CMTM4 is a subunit of the IL-17 receptor and mediates autoimmune pathology. Nat Immunol 2022; 23(11): 1644-52.

ROLE OF CMTM4 IN HELICOBACTER PYLORI INDUCED GASTRIC CANCER

Weiwei Fu 1, Xiurui Han 1, Shigang Ding 1

1 Peking University Third Hospital, Beijing, China

Event

UEG Week Copenhagen 2023

Topics

Colorectal Digestive Oncology Mechanisms & Personalised Medicine Stomach & H. Pylori

Submission format

Abstract

Session

Precision medicine of tomorrow in GI cancer

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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Early management/complications

Michael Fernandez Y Viesca 1

1 ERASME University Hospital, Brussels, Belgium

Event

UEG Postgraduate Teaching Programme 2023

Topics

Pancreas

Session

Severe acute pancreatitis: Management and complications

Published

2023

UEG Presentation

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Is gastroparesis a marker of panenteric motility disorder?

Hubert Louis 1

1 Erasme Hospital, Brussels, Belgium

Event

UEG Week Copenhagen 2023

Topics

Neurogastroenterology & Motility Oesophagus Stomach & H. Pylori

Session

When the twain shall meet: What upper and lower GI experts can learn from each other

Published

2023

UEG Presentation

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Summary: Safe feeding

Simon Lal 1, Loris Pironi 2

1 Salford Royal Foundation Trust, Salford, United Kingdom

2 University of Bologna S. Orsola-Malpighi Hospital, Bologna, Italy

Event

UEG Postgraduate Teaching Programme 2023

Topics

Small Intestine & Nutrition

Session

Safe feeding

Published

2023

UEG Presentation

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NICE diet

Sanna Nybacka 1

1 University of Gothenburg, Gothenburg, Sweden

Event

UEG Week Copenhagen 2023

Topics

Small Intestine & Nutrition Education & Training Neurogastroenterology & Motility

Session

Dietary advice for functional gastrointestinal disorders

Published

2023

UEG Presentation

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DUPILUMAB EFFICACY AND SAFETY UP TO 52 WEEKS IN ADULT AND ADOLESCENT PATIENTS WITH EOSINOPHILIC ESOPHAGITIS: RESULTS FROM PARTS B AND C OF THE RANDOMIZED, PLACEBO-CONTROLLED, THREE-PART, PHASE 3 LIBERTY EOE TREET STUDY

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Introduction

In Parts A and B of the 3-part phase 3 LIBERTY EoE TREET study (NCT03633617), dupilumab 300 mg weekly (DPL qw) vs placebo (PBO) demonstrated significant efficacy and acceptable safety up to 24 weeks in adults and adolescents with eosinophilic esophagitis (EoE). For patients who completed Parts A and B, Part C was an extended active treatment period for 28 weeks with patients receiving treatment up to 52 weeks. We previously reported continued improvements in all aspects of disease up to 52 weeks in DPL patients who completed Part A/C, and that PBO patients from Part A who received DPL in Part C showed similar efficacy. Here we present results from patients who completed Part B and continued to Part C, which assessed efficacy and safety of DPL up to 52 weeks in a larger number of patients.

Aims & Methods

Of 80 DPL qw patients in Part B, 74 continued DPL qw in Part C (DPL/DPL). Of 79 PBO patients in Part B, 37 received DPL qw in Part C (PBO/DPL). Part B co-primary endpoints were proportion of patients achieving peak esophageal intraepithelial eosinophil (eos) count ≤6 eos/high power field (hpf) and absolute change from Part B baseline (BL) in Dysphagia Symptom Score (DSQ) score at Week 24. Secondary endpoints are listed in the Table. In Part C, all endpoints were assessed at Week 52 as secondary endpoints. Safety was also assessed.

Table. Summary of co-primary and secondary endpoints at Weeks 24 (Part B) and 52 (Part C) of the 3-part phase 3 LIBERTY EoE TREET study.

	Wk 24 (Part B) DPL 300mg qw (n=80)	Wk 24 (Part B) PBO (n=79)	Wk 52 (Part C [patients from Part B]) DPL 300 mg qw /DPL 300 mg qw (n=74)	Wk 52 (Part C [patients from Part B]) PBO /DPL 300 mg qw (n=37)
Proportion of patients achieving peak eosinophil count of ≤6 eos/hpf Part B baseline, mean, eos/hpf (SD) n Proportion of patients achieving peak eosinophil count of ≤6 eos/hpf, n (%) Difference dupilumab vs placebo (95% CI) P value	89.2 (46.67) 80 47 (58.8) 53.5 (41.20–65.79) <0.0001	84.3 (41.20) 79 5 (6.3)	65^a 55 (84.6)	37^a 25 (67.6)
Absolute change from Part B baseline in DSQ score Part B baseline, mean (SD) n/imputed pts^b LS mean (SE)/mean (SD)^c Difference dupilumab vs placebo (95% CI) P value	38.4 (10.71) 63/17 −23.78 (1.86) −9.92 (−14.81 to −5.02) <0.0001	36.1 (10.55) 59/19 −13.86 (1.91)	54^a −30.26 (15.39)	24^a −27.25 (11.46)
Absolute change from Part B baseline in total EoE-EREFS Part B baseline, mean (SD) n/imputed pts^b LS mean (SE)/mean (SD)^c Difference dupilumab vs placebo (95% CI) P value	6.8 (2.96) 69/9 –4.5 (0.36) –3.8 (–4.77 to –2.93) <0.0001^d	7.2 (3.34) 68/11 –0.6 (0.38)	63^a –5.3 (2.85)	37^a –6.1 (3.60)
Percent change from Part B baseline in peak eos count (eos/hpf) n/imputed pts^b LS mean (SE)/mean (SD)^c Difference dupilumab vs placebo (95% CI) P value	71/9 −80.24 (8.34) −88.62 (−112.19 to −65.05) <0.0001^d	69/10 8.38 (10.09)	65^a −95.85 (4.04)	37^a −84.21 (42.17)
Absolute change from Part B baseline in EoE-HSS grade score Part B baseline, mean (SD) n/imputed pts^b LS mean (SE)/mean (SD)^c Difference dupilumab vs placebo (95% CI) P value Absolute change from Part B baseline in EoE-HSS stage score Part B baseline, mean (SD) n/imputed pts^b LS mean (SE)/mean (SD)^c Difference dupilumab vs placebo (95% CI) P value	1.31 (0.39) 71/9 –0.83 (0.04) –0.68 (−0.79 to −0.57) <0.0001^d 1.29 (0.33) 71/9 –0.80 (0.04) –0.67 (–0.78, –0.57) <0.0001^d	1.23 (0.40) 69/10 –0.15 (0.05) 1.22 (0.36) 69/10 –0.13 (0.04)	65^a –0.97 (0.43) 65^a –0.93 (0.37)	37^a –0.91 (0.39) 37^a –0.87 (0.35)
Percent change from Part B baseline in DSQ score n/imputed pts^b LS mean (SE)/mean (SD)^c Difference dupilumab vs placebo (95% CI) P value	63/17 –64.32 (5.07) –22.89 (–36.27 to –9.51) 0.0008	59/19 –41.43 (5.26)	54^a –80.74 (32.87)	24^a –78.13 (31.00)
Proportion of patients achieving peak eosinophil count of <15 eos/hpf n Proportion of patients achieving peak eosinophil count of <15 eos/hpf, n (%) Difference dupilumab vs placebo (95% CI) P value	80 66 (82.5) 74.9 (64.25–85.50) <0.0001^d	79 6 (7.6)	65^a 65 (100)	37^a 29 (78.4)
Relative change from Part B baseline in EDP gene signature n/imputed pts^b NES, median Difference dupilumab vs placebo (95% CI) P value	40/0 –2.67 –1.85 (–2.44, –1.15) <0.0001^d	41/0 –0.73	49^a –2.69	24^a –2.62
Relative change from Part B baseline in type 2 inflammation gene signature n/imputed pts^b NES, median Difference dupilumab vs placebo (95% CI) P value Part C analyses were purely descriptive. ^aNumber of patients with non-missing values at the visit. ^bIn Part B, values after first rescue treatment used were set to missing (censoring) and their Week 24 data were imputed; Part C summary is based on all observed values regardless of rescue treatment. ^cLS mean (SE) calculated for Part B; mean (SD) calculated for Part C. ^dNominal P value. CI, confidence interval; DSQ, Dysphagia Symptom Questionnaire; EDP, EoE Diagnostic Panel; EoE, eosinophilic esophagitis; EREFS, Endoscopic Reference Score; HSS, Histologic Scoring System; LS, least squares; NES, normalized enrichment score; pts, patients; SD, standard deviation; SE, standard error.	40/0 –1.93 –1.28 (–1.82, –1.07) <0.0001^d	41/0 –0.64	49^a –1.97	24^a –1.96

Results

Part B BL characteristics were similar across groups. At Week 52 of Part C, 84.6% of patients in the DPL/DPL and 67.6% of patients in the PBO/DPL groups achieved peak eos count of ≤6 eos/hpf and mean (SD) absolute change from Part B BL in DSQ score was −30.26 (15.39) for DPL/DPL and −27.25 (11.46) for PBO/DPL patients. At Week 52, 100% of patients in the DPL/DPL and 78.4% PBO/DPL groups achieved peak eos count of <15 eos/hpf. Compared to Part B BL, peak eos count, EREFS, HSS grade and stage scores were reduced, and EDP and T2 normalized enrichment scores were suppressed in the DPL/DPL and PBO/DPL groups at Week 52 (Table). Dupilumab demonstrated an acceptable safety profile in Part C; the most common (occurring ≥10%) treatment-emergent adverse events in the DPL/DPL and PBO/DPL groups were injection-site reactions (13.5% and 10.8%), COVID-19 (9.5% and 10.8%), and nasopharyngitis (4.1% and 10.8%).

Conclusion

As observed in Part A/C, dupilumab qw demonstrated persistent improvements in clinical, symptomatic, histologic, endoscopic, and molecular features of EoE up to 52 weeks and Overall safety was consistent with the known dupilumab safety profile. PBO patients from Part B who received dupilumab in Part C showed similar efficacy to dupilumab qw patients of Part B.

Disclosure

Dellon ES: Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Landos, LucidDx, Morphic, Nextstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio – consultant; Adare/Ellodi, Allakos, Arena, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda – research funding; Allakos, Holoclara, Invea – educational grant.
Rothenberg ME: Allakos, AstraZeneca, BMS, Celldex, ClostraBio, Ellodi Pharmaceuticals, GSK, Nextstone One, PulmOne, Regeneron Pharmaceuticals Inc., Revolo, Sanofi, Santa Ana Bio, Serpin Pharma, Spoon Guru ‒ consultant; Celldex, ClostraBio, Nextstone One, PulmOne, Santa Ana Bio, Serpin Pharma, Spoon Guru ‒ equity interest; Mapi Research Trust ‒ royalties from PEESSv2; Teva Pharmaceuticals ‒ royalties from reslizumab; UpToDate ‒ royalties; inventor of patents owned by Cincinnati Children’s Hospital.
Collins MH: Alimentiv, Allakos, Arena, AstraZeneca, BMS, Calypso, EsoCap, GSK, Regeneron Pharmaceuticals, Inc., Shire – consultant.
Hirano I: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eli Lilly, EsoCap, Gossamer Bio, GSK, Nexstone Immunology, Parexel/Calyx, Phathom, Receptos/BMS, Regeneron Pharmaceuticals Inc., Sanofi, Shire/Takeda – consultant; Adare/Ellodi, Allakos, Receptos/BMS, Regeneron Pharmaceuticals Inc., Shire/Takeda – research funding.
Chehade M: Adare/Ellodi, Allakos, AstraZeneca, BMS, Phathom; Recludix, Regeneron Pharmaceuticals Inc., Sanofi, Shire/Takeda – consultant; Adare/Ellodi, Allakos, AstraZeneca, Danone, Regeneron Pharmaceuticals Inc., Shire/Takeda – research funding.