Helicobacter pylori and immunotherapy for gastrointestinal cancer

Keren Jia; Yang Chen; Yi Xie; Xicheng Wang; Yajie Hu; Yu Sun; Yanshuo Cao; Liyan Zhang; Yakun Wang; Zhenghang Wang; Zhihao Lu; Jian Li; Xiaotian Zhang; Lin Shen

doi:10.1016/j.xinn.2023.100561

The Innovation > 2024 Vol. 5 > No. 2

Next Article Previous Article

ARTICLE Open Access

Cite PDF

Helicobacter pylori and immunotherapy for gastrointestinal cancer

1.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
2.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China

More Information

³These authors contributed equally
Corresponding author: shenlin@bjmu.edu.cn
Received Date: August 15, 2023

Accepted Date: December 29, 2023

Published Online: January 08, 2024

The Innovation 5(2), https://doi.org/10.1016/j.xinn.2023.100561 | Cite this article

GRAPHICAL ABSTRACT

GRAPHICAL ABSTRACT

DownLoad: Full size image

PUBLIC SUMMARY

PUBLIC SUMMARY
1. ■ Helicobacter pylori infection is a favorable factor for gastric cancer immunotherapy by shaping the "hot" tumor microenvironment.
2. ■ H. pylori infection is unfavorable for immunotherapy in DNA mismatch repair-deficient/microsatellite instability-high colon adenocarcinoma and esophageal squamous cell cancer.
3. ■ This study highlights the importance of the test for H. pylori infection in cancer patients treated with immunotherapy.

ABSTRACT

ABSTRACT

Helicobacter pylori infection is associated with the risk of gastrointestinal (GI) cancers; however, its impact on immunotherapy for GI cancers remains uncertain. In this study, we included 10,122 patients who underwent ¹³C-urea breath tests. Among 636 patients with Epstein-Barr virus–negative microsatellite-stable gastric cancer (GC) who were treated with anti-PD-1/PD-L1 therapy, H. pylori–positive patients exhibited significantly longer immune-related progression-free survival (irPFS) compared with H. pylori–negative patients (6.97 months versus 5.03 months, p < 0.001, hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.62–0.95, p = 0.015). Moreover, the H. pylori–positive group demonstrated a trend of 4 months longer median immune-related overall survival (irOS) than the H. pylori–negative group. H. pylori–positive GC displayed higher densities of PD-L1⁺ cells and nonexhausted CD8⁺ T cells, indicative of a "hot" tumor microenvironment. Transcriptomic analysis revealed that H. pylori–positive GC shared molecular characteristics similar to those of immunotherapy-sensitive GC. However, H. pylori–positive patients with DNA mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) colorectal adenocarcinoma and esophageal squamous cell carcinoma (ESCC) had shorter irPFS compared with H. pylori–negative patients (16.13 months versus not reached, p = 0.042, HR 2.26, 95% CI 1.13–4.50, p = 0.021 and 5.57 months versus 6.97 months, p = 0.029, HR 1.59, 95% CI 1.14–2.23, p = 0.006, respectively). The difference in irOS between H. pylori–positive and –negative patients had the same trend as that between dMMR/MSI-H colorectal adenocarcinoma and ESCC patients. We also identified a trend of shorter irPFS and irOS in H. pylori–positive liver cancer and pancreatic cancer patients. In summary, our findings supported that H. pylori infection is a beneficial factor for GC immunotherapy by shaping hot tumor microenvironments. However, in dMMR/MSI-H colorectal adenocarcinoma and ESCC patients, H. pylori adversely affects the efficacy of immunotherapy.

FullText(HTML)

REFERENCES

[1]	Li, Y., Choi, H., Leung, K., et al. (2023). Global prevalence of Helicobacter pylori infection between 1980 and 2022: a systematic review and meta-analysis. Lancet. Gastroenterol. Hepatol. 8: 553–564. https://doi.org/10.1016/S2468-1253(23)00070-5. View in Article CrossRef Google Scholar
[2]	Nomura, A., Stemmermann, G.N., Chyou, P.H., et al. (1991). Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N. Engl. J. Med. *325*: 1132–1136. https://doi.org/10.1056/NEJM199110173251604. View in Article CrossRef Google Scholar
[3]	Parsonnet, J., Friedman, G.D., Vandersteen, D.P., et al. (1991). Helicobacter pylori infection and the risk of gastric carcinoma. N. Engl. J. Med. *325*: 1127–1131. https://doi.org/10.1056/NEJM199110173251603. View in Article CrossRef Google Scholar
[4]	Xi, S., Jing, L., Lili, W., et al. (2022). Magnetic controlled capsule endoscope (MCCE)'s diagnostic performance for H. pylori infection status based on the Kyoto classification of gastritis. BMC Gastroenterol. 22: 502. https://doi.org/10.1186/s12876-022-02589-z. View in Article CrossRef Google Scholar
[5]	Ağagündüz, D., Cocozza, E., Cemali, Ö., et al. (2023). Understanding the role of the gut microbiome in gastrointestinal cancer: A review. Front. Pharmacol. 14: 1130562. https://doi.org/10.3389/fphar.2023.1130562. View in Article CrossRef Google Scholar
[6]	Öztekin, M., Yılmaz, B., Ağagündüz, D., et al. (2021). Overview of Helicobacter pylori Infection: Clinical Features, Treatment, and Nutritional Aspects. Diseases 9: 66. https://doi.org/10.3390/diseases9040066. View in Article CrossRef Google Scholar
[7]	Ralser, A., Dietl, A., Jarosch, S., et al. (2023). Helicobacter pylori promotes colorectal carcinogenesis by deregulating intestinal immunity and inducing a mucus-degrading microbiota signature. Gut 72: 1258–1270. https://doi.org/10.1136/gutjnl-2022-328075. View in Article CrossRef Google Scholar
[8]	Liu, I.L., Tsai, C.H., Hsu, C.H., et al. (2019). Helicobacter pylori infection and the risk of colorectal cancer: a nationwide population-based cohort study. QJM *112*: 787–792. https://doi.org/10.1093/qjmed/hcz157. View in Article CrossRef Google Scholar
[9]	Amieva, M., and Peek, R.M., Jr. (2016). Pathobiology of Helicobacter pylori-Induced Gastric Cancer. Gastroenterology *150*: 64–78. https://doi.org/10.1053/j.gastro.2015.09.004. View in Article CrossRef Google Scholar
[10]	Xie, F.J., Zhang, Y.P., Zheng, Q.Q., et al. (2013). Helicobacter pylori infection and esophageal cancer risk: an updated meta-analysis. World J. Gastroenterol. 19: 6098–6107. https://doi.org/10.3748/wjg.v19.i36.6098. View in Article CrossRef Google Scholar
[11]	Rokkas, T., Pistiolas, D., Sechopoulos, P., et al. (2007). Relationship between Helicobacter pylori infection and esophageal neoplasia: a meta-analysis. Clin. Gastroenterol. Hepatol. 5: 1413-7–1417.e1-2. https://doi.org/10.1016/j.cgh.2007.08.010. View in Article CrossRef Google Scholar
[12]	You, W.C., Brown, L.M., Zhang, L., et al. (2006). Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions. J. Natl. Cancer Inst. 98: 974–983. https://doi.org/10.1093/jnci/djj264. View in Article CrossRef Google Scholar
[13]	Choi, I.J., Kook, M.C., Kim, Y.I., et al. (2018). Helicobacter pylori Therapy for the Prevention of Metachronous Gastric Cancer. N. Engl. J. Med. *378*: 1085–1095. https://doi.org/10.1056/NEJMoa1708423. View in Article CrossRef Google Scholar
[14]	Choi, I.J., Kim, C.G., Lee, J.Y., et al. (2020). Family History of Gastric Cancer and Helicobacter pylori Treatment. N. Engl. J. Med. *382*: 427–436. https://doi.org/10.1056/NEJMoa1909666. View in Article CrossRef Google Scholar
[15]	Li, W.Q., Zhang, J.Y., Ma, J.L., et al. (2019). Effects of Helicobacter pylori treatment and vitamin and garlic supplementation on gastric cancer incidence and mortality: follow-up of a randomized intervention trial. BMJ *366*: l5016. https://doi.org/10.1136/bmj.l5016. View in Article CrossRef Google Scholar
[16]	Ye, Y., Zhang, Y., Yang, N., et al. (2022). Profiling of immune features to predict immunotherapy efficacy. Innovation 3: 100194. https://doi.org/10.1016/j.xinn.2021.100194. View in Article CrossRef Google Scholar
[17]	Lu, Z., Peng, Z., Liu, C., et al. (2020). Current Status and Future Perspective of Immunotherapy in Gastrointestinal Cancers. Innovation 1: 100041. https://doi.org/10.1016/j.xinn.2020.100041. View in Article CrossRef Google Scholar
[18]	Kang, Y.K., Chen, L.T., Ryu, M.H., et al. (2022). Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 23: 234–247. https://doi.org/10.1016/S1470-2045(21)00692-6. View in Article CrossRef Google Scholar
[19]	Janjigian, Y.Y., Shitara, K., Moehler, M., et al. (2021). First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet *398*: 27–40. https://doi.org/10.1016/S0140-6736(21)00797-2. View in Article CrossRef Google Scholar
[20]	Lu, Z., Wang, J., Shu, Y., et al. (2022). Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ *377*: e068714. https://doi.org/10.1136/bmj-2021-068714. View in Article CrossRef Google Scholar
[21]	Li, J., Deng, Y., Zhang, W., et al. (2021). Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors. J. Hematol. Oncol. 14: 95. https://doi.org/10.1186/s13045-021-01095-1. View in Article CrossRef Google Scholar
[22]	Yuan, J., Bao, P., Chen, Z., et al. (2023). Advanced prompting as a catalyst: Empowering large language models in the management of gastrointestinal cancers. Innovat. Med. 1: 100019. https://doi.org/10.59717/j.xinn-med.2023.100019. View in Article CrossRef Google Scholar
[23]	Lee, J., Nebozhyn, M., et al. (2015). Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat. Med. 21: 449–456. https://doi.org/10.1038/nm.3850. View in Article CrossRef Google Scholar
[24]	Le, D.T., Kim, T.W., Van Cutsem, E., et al. (2020). Phase Ⅱ Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164. J. Clin. Oncol. 38: 11–19. https://doi.org/10.1200/JCO.19.02107. View in Article CrossRef Google Scholar
[25]	Maio, M., Ascierto, P.A., Manzyuk, L., et al. (2022). Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase Ⅱ KEYNOTE-158 study. Ann. Oncol. 33: 929–938. https://doi.org/10.1016/j.annonc.2022.05.519. View in Article CrossRef Google Scholar
[26]	Naseem, M., Barzi, A., Brezden-Masley, C., et al. (2018). Outlooks on Epstein-Barr virus associated gastric cancer. Cancer Treat Rev. 66: 15–22. https://doi.org/10.1016/j.ctrv.2018. 03.006. View in Article CrossRef Google Scholar
[27]	Chen, Y., Jia, K., Sun, Y., et al. (2022). Predicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment. Nat. Commun. 13: 4851. https://doi.org/10.1038/s41467-022-32570-z. View in Article CrossRef Google Scholar
[28]	Wang, J., Ge, J., Wang, Y., et al. (2022). EBV miRNAs BART11 and BART17-3p promote immune escape through the enhancer-mediated transcription of PD-L1. Nat. Commun. 13: 866. https://doi.org/10.1038/s41467-022-28479-2. View in Article CrossRef Google Scholar
[29]	Zhu, Y., Zhu, F., Ba, H., et al. (2023). Helicobacter pylori infection and PD-L1 expression in gastric cancer: A meta-analysis. Eur. J. Clin. Invest. 53: e13880. https://doi.org/10.1111/eci.13880. View in Article CrossRef Google Scholar
[30]	Derks, S., de Klerk, L.K., Xu, X., et al. (2020). Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas. Ann. Oncol. 31: 1011–1020. https://doi.org/10.1016/j.annonc.2020.04.011. View in Article CrossRef Google Scholar
[31]	André, T., Shiu, K.K., Kim, T.W., et al. (2020). Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N. Engl. J. Med. *383*: 2207–2218. https://doi.org/10.1056/NEJMoa2017699. View in Article CrossRef Google Scholar
[32]	Joensuu, H., Hohenberger, P., and Corless, C.L. (2013). Gastrointestinal stromal tumour. Lancet *382*: 973–983. https://doi.org/10.1016/S0140-6736(13)60106-3. View in Article CrossRef Google Scholar
[33]	Rindi, G., Mete, O., Uccella, S., et al. (2022). Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms. Endocr. Pathol. 33: 115–154. https://doi.org/10.1007/s12022-022-09708-2. View in Article CrossRef Google Scholar
[34]	Oster, P., Vaillant, L., Riva, E., et al. (2022). Helicobacter pylori infection has a detrimental impact on the efficacy of cancer immunotherapies. Gut 71: 457–466. https://doi.org/10.1136/gutjnl-2020-323392. View in Article CrossRef Google Scholar
[35]	Janjigian, Y.Y., Shitara, K., Ajani, J., et al. (2023). Abstract CT037: Nivolumab plus ipilimumab vs chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: CheckMate 649 biomarker analyses. Cancer Res. 83: CT037. https://doi.org/10.1158/1538-7445.AM2023-CT037. View in Article CrossRef Google Scholar
[36]	Kim, T.K., Vandsemb, E.N., Herbst, R.S., and Chen, L. (2022). Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities. Nat. Rev. Drug Discov. 21: 529–540. https://doi.org/10.1038/s41573-022-00493-5. View in Article CrossRef Google Scholar
[37]	Gerard, C.L., Delyon, J., Wicky, A., et al. (2021). Turning tumors from cold to inflamed to improve immunotherapy response. Cancer Treat Rev. *101*: 102227. https://doi.org/10.1016/j.ctrv.2021.102227. View in Article CrossRef Google Scholar
[38]	Fu, L., and Xie, C. (2019). A lucid review of Helicobacter pylori-induced DNA damage in gastric cancer. Helicobacter 24: e12631. https://doi.org/10.1111/hel.12631. View in Article CrossRef Google Scholar
[39]	Baj, J., Korona-Głowniak, I., Forma, A., et al. (2020). Mechanisms of the Epithelial-Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer. Cells 9: 1055. https://doi.org/10.3390/cells9041055. View in Article CrossRef Google Scholar
[40]	Krzysiek-Maczka, G., Targosz, A., Szczyrk, U., et al. (2018). Role of Helicobacter pylori infection in cancer-associated fibroblast-induced epithelial-mesenchymal transition in vitro. Helicobacter 23: e12538. https://doi.org/10.1111/hel.12538. View in Article CrossRef Google Scholar
[41]	Gao, J.J., Zhang, Y., Gerhard, M., et al. (2018). Association Between Gut Microbiota and Helicobacter pylori-Related Gastric Lesions in a High-Risk Population of Gastric Cancer. Front. Cell. Infect. Microbiol. 8: 202. https://doi.org/10.3389/fcimb.2018.00202. View in Article CrossRef Google Scholar
[42]	Zhu, L., Huang, Y., Li, H., and Shao, S. (2022). Helicobacter pylori promotes gastric cancer progression through the tumor microenvironment. Appl. Microbiol. Biotechnol. *106*: 4375–4385. https://doi.org/10.1007/s00253-022-12011-z. View in Article CrossRef Google Scholar
[43]	Schenkel, J.M., and Pauken, K.E. (2023). Localization, tissue biology and T cell state - implications for cancer immunotherapy. Nat. Rev. Immunol. 23: 807–823. https://doi.org/10.1038/s41577-023-00884-8. View in Article CrossRef Google Scholar
[44]	Banchereau, R., Chitre, A.S., Scherl, A., et al. (2021). Intratumoral CD103+ CD8+ T cells predict response to PD-L1 blockade. J. Immunother. Cancer 9: e002231. https://doi.org/10.1136/jitc-2020-002231. View in Article CrossRef Google Scholar
[45]	Pabla, S., Conroy, J.M., Nesline, M.K., et al. (2019). Proliferative potential and resistance to immune checkpoint blockade in lung cancer patients. J. Immunother. Cancer 7: 27. https://doi.org/10.1186/s40425-019-0506-3. View in Article CrossRef Google Scholar
[46]	Buechler, M.B., Pradhan, R.N., Krishnamurty, A.T., et al. (2021). Cross-tissue organization of the fibroblast lineage. Nature *593*: 575–579. https://doi.org/10.1038/s41586-021-03549-5. View in Article CrossRef Google Scholar
[47]	Chen, Y., McAndrews, K.M., and Kalluri, R. (2021). Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat. Rev. Clin. Oncol. 18: 792–804. https://doi.org/10.1038/s41571-021-00546-5. View in Article CrossRef Google Scholar
[48]	Ganesh, K., Stadler, Z.K., Cercek, A., et al. (2019). Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat. Rev. Gastroenterol. Hepatol. 16: 361–375. https://doi.org/10.1038/s41575-019-0126-x. View in Article CrossRef Google Scholar
[49]	Diaz, L.A., Jr., Shiu, K.K., Kim, T.W., et al. (2022). Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 23: 659–670. https://doi.org/10.1016/S1470-2045(22)00197-8. View in Article CrossRef Google Scholar
[50]	Chen, C.C., Liou, J.M., Lee, Y.C., et al. (2021). The interplay between Helicobacter pylori and gastrointestinal microbiota. Gut Microb. 13: 1–22. https://doi.org/10.1080/19490976.2021.1909459. View in Article CrossRef Google Scholar
[51]	Hänzelmann, S., Castelo, R., and Guinney, J. (2013). GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinf. 14: 7. https://doi.org/10.1186/1471-2105-14-7. View in Article CrossRef Google Scholar
[52]	R Core Team, R. (2013). R: A Language and Environment for Statistical Computing (Scientific Research Publishing). View in Article Google Scholar

Cited by

ABOUT THIS ARTICLE

Cite this article:

Keren Jia, Yang Chen, Yi Xie, Xicheng Wang, Yajie Hu, Yu Sun, Yanshuo Cao, Liyan Zhang, Yakun Wang, Zhenghang Wang, Zhihao Lu, Jian Li, Xiaotian Zhang, Lin Shen. Helicobacter pylori and immunotherapy for gastrointestinal cancer[J]. The Innovation, 2024, 5(2). https://doi.org/10.1016/j.xinn.2023.100561

Keren Jia, Yang Chen, Yi Xie, Xicheng Wang, Yajie Hu, Yu Sun, Yanshuo Cao, Liyan Zhang, Yakun Wang, Zhenghang Wang, Zhihao Lu, Jian Li, Xiaotian Zhang, Lin Shen. Helicobacter pylori and immunotherapy for gastrointestinal cancer[J]. The Innovation, 2024, 5(2). https://doi.org/10.1016/j.xinn.2023.100561

Welcome!

To request copyright permission to republish or share portions of our works, please visit Copyright Clearance Center's (CCC) Marketplace website at marketplace.copyright.com.

PDF

Figures(5) Tables(3)

Article Metrics

Article views(5902) PDF downloads(1909)

Helicobacter pylori and immunotherapy for gastrointestinal cancer

GRAPHICAL ABSTRACT

PUBLIC SUMMARY

ABSTRACT

REFERENCES

ABOUT THIS ARTICLE

Cite this article:

Welcome!

Share

Article Metrics

Relative Articles

Cited by

Catalog

{{newsColumn.name}}

Official Account

{{newsColumn.name}}

Collections

Stay connected

{{newsColumn.name}}

Helicobacter pylori and immunotherapy for gastrointestinal cancer

GRAPHICAL ABSTRACT

PUBLIC SUMMARY

ABSTRACT

REFERENCES

ABOUT THIS ARTICLE

Cite this article:

Welcome!

Share

Article Metrics

Relative Articles

Cited by

Catalog

Export File

Citation

Format

Content

{{newsColumn.name}}

Official Account

{{newsColumn.name}}

Collections

Stay connected

{{newsColumn.name}}