Meta-Analysis

Impact of Helicobacter pylori infection on the efficacy of immune checkpoint inhibitors for cancer treatment: a meta-analysis

Maryam Noori‡

Farimah Fayyaz‡

Nima Rezaei

Maryam Noori‡

https://orcid.org/0000-0001-7230-8934

Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

Urology Research Center, Tehran University of Medical Science, Tehran, Iran

‡Authors contributed equally

Search for more papers by this author

Farimah Fayyaz‡

https://orcid.org/0000-0002-5692-0370

Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran

Cancer Immunology Project (CIP), Universal Scientific Education & Research Network (USERN), Tehran, Iran

Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran

‡Authors contributed equally

Search for more papers by this author

Nima Rezaei

*Author for correspondence: Tel.: +98 21 6692 9234;

E-mail Address: rezaei_nima@tums.ac.ir

https://orcid.org/0000-0002-3836-1827

Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran

Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran

Search for more papers by this author

Published Online:4 May 2023https://doi.org/10.2217/imt-2022-0250

View article

Abstract

Aim: The present systematic review and meta-analysis was designed to assess the impact of Helicobacter pylori infection on the efficacy of immune checkpoint inhibitors (ICIs). Materials & methods: PubMed, Scopus, Web of Science and EMBASE databases were systematically searched up to 1 February 2023. Results: Three studies comprising 263 patients treated with ICIs were included. The results of pooled analysis showed that H. pylori infection was associated with reduced overall survival and progression-free survival. Furthermore, the rate of progressive disease after administration of ICIs was higher in H. pylori-positive patients relative to H. pylori-negative patients. Conclusion:H. pylori infection status is a novel potential response biomarker for predicting the efficacy of ICIs in different cancers.

Plain language summary

Immune checkpoint inhibitors (ICIs) are a novel treatment modality for cancer patients. The efficacy of this kind of treatment can be affected by several factors. The present systematic review and meta-analysis was designed to evaluate the impact of infection by Helicobacter pylori on the outcomes of patients undergoing ICI therapy. Those patients who were affected by H. pylori had an increased rate of mortality and disease progression after ICI therapy relative to those who were not affected at the time of treatment. As a result, the findings highlight that H. pylori infection reduces the effectiveness of immunotherapy with ICIs.

Tweetable abstract

In the present systematic review, the authors show that infection by Helicobacter pylori reduces the efficacy of immune checkpoint inhibitors for patients with cancer. #immune_checkpoint_inhibitor #helicobacter_pylori #cancer.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Sung H, Ferlay J, Siegel RL et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71(3), 209–249 (2021).
MedlineGoogle Scholar
2. de Oliveira SA, Borges R, dos Santos Rosa D et al. Strategies for cancer treatment based on photonic nanomedicine. Materials 14(6), 1435 (2021).
Medline CASGoogle Scholar
3. Vinay DS, Ryan EP, Pawelec G et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin. Cancer Biol. 35, S185–S198 (2015).
MedlineGoogle Scholar
4. Marin-Acevedo JA, Kimbrough EO, Lou Y. Next generation of immune checkpoint inhibitors and beyond. J. Hematol. Oncol. 14(1), 45 (2021).
Medline CASGoogle Scholar
5. Kaushik I, Ramachandran S, Zabel C, Gaikwad S, Srivastava SK. The evolutionary legacy of immune checkpoint inhibitors. Semin. Cancer Biol. 86(Pt 2), 491–498 (2022).
Medline CASGoogle Scholar
6. Naimi A, Mohammed RN, Raji A et al. Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons. Cell Commun. Signal. 20(1), 1–31 (2022).
MedlineGoogle Scholar
7. Ledford H. Melanoma drug wins US approval. Nature 471(7340), 561–561 (2011).
Medline CASGoogle Scholar
8. Herzberg B, Campo MJ, Gainor JF. Immune checkpoint inhibitors in non-small cell lung cancer. Oncologist 22(1), 81–88 (2017).
Medline CASGoogle Scholar
9. Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet 398(10304), 1002–1014 (2021).
Medline CASGoogle Scholar
10. Swoboda A, Nanda R. Immune checkpoint blockade for breast cancer. Optim. Breast Cancer Manag. 173, 155–165 (2018). • Reviews the impact of gut microbiota on the initiation of cancers, its association with host immunity and its beneficial functions in the modulation of cancer immunotherapy responses.
Google Scholar
11. Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Ann. Rev. Pathol. 16, 223–249 (2021).
Medline CASGoogle Scholar
12. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 359(6382), 1350–1355 (2018). •• Evaluated the impact of Helicobacter pylori infection on the efficacy of immunotherapeutic agents in both mouse models and cohorts of non-small-cell lung cancer.
Medline CASGoogle Scholar
13. Shum B, Larkin J, Turajlic S. Predictive biomarkers for response to immune checkpoint inhibition. Semin. Cancer Biol. 79, 4–17 (2022). • Contains a scientometric analysis visualizing the research hotspots and trends in H. pylori and immunotherapy.
Medline CASGoogle Scholar
14. Davis AA, Patel VG. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J. Immunother. Cancer 7(1), 1–8 (2019).
MedlineGoogle Scholar
15. Klempner SJ, Fabrizio D, Bane S et al. Tumor mutational burden as a predictive biomarker for response to immune checkpoint inhibitors: a review of current evidence. Oncologist 25(1), e147–e159 (2020).
MedlineGoogle Scholar
16. Abida W, Cheng ML, Armenia J et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 5(4), 471–478 (2019).
MedlineGoogle Scholar
17. Rezasoltani S, Yadegar A, Aghdaei HA, Zali MR. Modulatory effects of gut microbiome in cancer immunotherapy: a novel paradigm for blockade of immune checkpoint inhibitors. Cancer Med. 10(3), 1141–1154 (2021).
Medline CASGoogle Scholar
18. Routy B, Le Chatelier E, Derosa L et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science 359(6371), 91–97 (2018).
Medline CASGoogle Scholar
19. Spencer CN, Gopalakrishnan V, Mcquade J et al. Abstract 2838: the gut microbiome (GM) and immunotherapy response are influenced by host lifestyle factors. Cancer Res. 79(Suppl. 13), 2838–2838 (2019).
Google Scholar
20. Pinato DJ, Howlett S, Ottaviani D et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol. 5(12), 1774–1778 (2019).
MedlineGoogle Scholar
21. Zamani M, Ebrahimtabar F, Zamani V et al. Systematic review with meta-analysis: the worldwide prevalence of Helicobacter pylori infection. Aliment. Pharmacol. Ther. 47(7), 868–876 (2018).
Medline CASGoogle Scholar
22. Mukaisho K-I, Nakayama T, Hagiwara T, Hattori T, Sugihara H. Two distinct etiologies of gastric cardia adenocarcinoma: interactions among pH, Helicobacter pylori, and bile acids. Front. Microbiol. 6, 412 (2015).
MedlineGoogle Scholar
23. Oster P, Vaillant L, Riva E et al. Helicobacter pylori infection has a detrimental impact on the efficacy of cancer immunotherapies. Gut 71(3), 457–466 (2022).
Medline CASGoogle Scholar
24. Arnold IC, Müller A. Helicobacter pylori: does gastritis prevent colitis? Inflamm. Intest. Dis. 1(3), 102–112 (2016).
MedlineGoogle Scholar
25. Dellon ES, Peery AF, Shaheen NJ et al. Inverse association of esophageal eosinophilia with Helicobacter pylori based on analysis of a US pathology database. Gastroenterology 141(5), 1586–1592 (2011).
MedlineGoogle Scholar
26. Shirzad-Aski H, Besharat S, Kienesberger S et al. Association between Helicobacter pylori colonization and inflammatory bowel disease: a systematic review and meta-analysis. J. Clin. Gastroenterol. 55(5), 380–392 (2021).
Medline CASGoogle Scholar
27. Chen Y, Blaser MJ. Inverse associations of Helicobacter pylori with asthma and allergy. Arch. Intern. Med. 167(8), 821–827 (2007).
MedlineGoogle Scholar
28. Shi Y, Zheng H, Guo Z et al. Effect of Helicobacter pylori on immunotherapy is gaining more attention. Helicobacter 27(5), e12925 (2022).
Medline CASGoogle Scholar
29. Page MJ, Mckenzie JE, Bossuyt PM et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372, n71 (2021).
MedlineGoogle Scholar
30. Wells GA, Shea B, O’Connell D et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses (2000). www.ohri.ca/programs/clinical_epidemiology/oxford.asp
Google Scholar
31. Higgins JP, Thomas J, Chandler J et al. Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons, NJ, USA (2019).
Google Scholar
32. Sterne JAC, Sutton AJ, Ioannidis JPA et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 343, d4002 (2011).
MedlineGoogle Scholar
33. Che H, Xiong Q, Ma J et al. Association of Helicobacter pylori infection with survival outcomes in advanced gastric cancer patients treated with immune checkpoint inhibitors. BMC Cancer 22(1), 904 (2022).
Medline CASGoogle Scholar
34. Tonneau M, Nolin-Lapalme A, Kazandjian S et al. Helicobacter pylori serology is associated with worse overall survival in patients with melanoma treated with immune checkpoint inhibitors. Oncoimmunology 11(1), 2096535 (2022).
MedlineGoogle Scholar
35. Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8(9), 1069–1086 (2018).
MedlineGoogle Scholar
36. Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br. J. Cancer 118(1), 9–16 (2018).
Medline CASGoogle Scholar
37. Hayase E, Jenq RR. Role of the intestinal microbiome and microbial-derived metabolites in immune checkpoint blockade immunotherapy of cancer. Genome Med. 13(1), 1–11 (2021).
MedlineGoogle Scholar
38. Derosa L, Routy B, Desilets A et al. Microbiota-centered interventions: the next breakthrough in immuno-oncology? Cancer Discov. 11(10), 2396–2412 (2021).
Medline CASGoogle Scholar
39. Vétizou M, Pitt JM, Daillère R et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350(6264), 1079–1084 (2015).
Medline CASGoogle Scholar
40. Sivan A, Corrales L, Hubert N et al. Commensal bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy. Science 350(6264), 1084–1089 (2015).
Medline CASGoogle Scholar
41. Gopalakrishnan V, Spencer CN, Nezi L et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359(6371), 97–103 (2018). •• This review article highlights the effects of H. pylori on the immune microenvironment and its potential roles in tumor immunotherapy responses.
Medline CASGoogle Scholar
42. Chaput N, Lepage P, Coutzac C et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann. Oncol. 28(6), 1368–1379 (2017).
Medline CASGoogle Scholar
43. Gopalakrishnan V, Spencer CN, Nezi L et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359(6371), 97–103 (2018).
Medline CASGoogle Scholar
44. Matson V, Fessler J, Bao R et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359(6371), 104–108 (2018). •• This article provides a hypothesis regarding the favorable effect of H. pylori infection on outcomes of gastric cancer patients undergoing immune checkpoint inhibitor therapy.
Medline CASGoogle Scholar
45. Jiang S, Geng S, Chen Q et al. Effects of concomitant antibiotics use on immune checkpoint inhibitor efficacy in cancer patients. Front. Oncol. 12, 823705 (2022).
MedlineGoogle Scholar
46. Eng L, Sutradhar R, Niu Y et al. Impact of antibiotic exposure before immune checkpoint inhibitor treatment on overall survival in older adults with cancer: a population-based study. J. Clin. Oncol. doi: 10.1200/JCO.22.00074 JCO.22.00074 (2023).
Google Scholar
47. Moyat M, Velin D. Immune responses to Helicobacter pylori infection. World J. Gastroenterol. 20(19), 5583–5593 (2014).
Medline CASGoogle Scholar
48. Altobelli A, Bauer M, Velez K, Cover TL, Müller A. Helicobacter pylori VacA targets myeloid cells in the gastric lamina propria to promote peripherally induced regulatory T-cell differentiation and persistent infection. MBio 10(2), e00261–00219 (2019).
Medline CASGoogle Scholar
49. Arnold IC, Zhang X, Artola-Boran M et al. BATF3-dependent dendritic cells drive both effector and regulatory T-cell responses in bacterially infected tissues. PLoS Pathog. 15(6), e1007866 (2019).
Medline CASGoogle Scholar
50. Engler DB, Reuter S, van Wijck Y et al. Effective treatment of allergic airway inflammation with Helicobacter pylori immunomodulators requires BATF3-dependent dendritic cells and IL-10. Proc. Natl Acad. Sci. 111(32), 11810–11815 (2014).
Medline CASGoogle Scholar
51. Zhuang Y, Cheng P, Liu X-F et al. A pro-inflammatory role for Th22 cells in Helicobacter pylori-associated gastritis. Gut 64(9), 1368–1378 (2015).
Medline CASGoogle Scholar
52. Oertli M, Sundquist M, Hitzler I et al. DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection. J. Clin. Investig. 122(3), 1082–1096 (2012).
Medline CASGoogle Scholar
53. Oertli M, Noben M, Engler DB et al. Helicobacter pylori γ-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proc. Natl Acad. Sci. USA 110(8), 3047–3052 (2013).
Medline CASGoogle Scholar
54. Koch KN, Hartung ML, Urban S et al. Helicobacter urease–induced activation of the TLR2/NLRP3/IL-18 axis protects against asthma. J. Clin. Investig. 125(8), 3297–3302 (2015).
MedlineGoogle Scholar
55. Reyes VE, Peniche AG. Helicobacter pylori deregulates T and B cell signaling to trigger immune evasion. In: Molecular Mechanisms of Inflammation: Induction, Resolution and Escape by Helicobacter pylori. Backert S (Ed.). Springer International Publishing, Cham, Switzerland, 229–265 (2019).
Google Scholar
56. Maldonado-Contreras A, Goldfarb KC, Godoy-Vitorino F et al. Structure of the human gastric bacterial community in relation to Helicobacter pylori status. ISME J. 5(4), 574–579 (2011).
Medline CASGoogle Scholar
57. Heimesaat MM, Fischer A, Plickert R et al. Helicobacter pylori-induced gastric immunopathology is associated with distinct microbiota changes in the large intestines of long-term infected Mongolian gerbils. PLOS ONE 9(6), e100362 (2014).
MedlineGoogle Scholar
58. Deng R, Zheng H, Cai H, Li M, Shi Y, Ding S. Effects of helicobacter pylori on tumor microenvironment and immunotherapy responses. Front. Immunol. 13, 923477 (2022).
Medline CASGoogle Scholar
59. Xue L-J, Mao X-B, Liu X-B et al. Activation of CD3+ T cells by Helicobacter pylori DNA vaccines in potential immunotherapy of gastric carcinoma. Cancer Biol. Ther. 20(6), 866–876 (2019).
Medline CASGoogle Scholar
60. Holokai L, Chakrabarti J, Broda T et al. Increased programmed death-ligand 1 is an early epithelial cell response to Helicobacter pylori infection. PLoS Pathog. 15(1), e1007468 (2019).
MedlineGoogle Scholar
61. Zhang M-J, Chen D-S, Li S, Chen L, Qi Y-X, Zhang C-J. Helicobacter pylori infection as a potential favorable factor for immune checkpoint inhibitor therapy for gastric cancer. Invest. New Drugs 39(5), 1436–1438 (2021).
Medline CASGoogle Scholar
62. Aydın EM, Demir TD, Seymen N et al. The crosstalk between H. pylori virulence factors and the PD1:PD-L1 immune checkpoint inhibitors in progression to gastric cancer. Immunol. Lett. 239, 1–11 (2021).
Medline CASGoogle Scholar
63. Sitkin S, Lazebnik L, Avalueva E, Kononova S, Vakhitov T. Gastrointestinal microbiome and Helicobacter pylori: eradicate, leave it as it is, or take a personalized benefit–risk approach? World J. Gastroenterol. 28(7), 766 (2022).
Medline CASGoogle Scholar
64. Tsikala-Vafea M, Belani N, Vieira K, Khan H, Farmakiotis D. Use of antibiotics is associated with worse clinical outcomes in patients with cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Intl J. Infect. Dis. 106, 142–154 (2021).
Medline CASGoogle Scholar

Vol. 15, No. 9

Supplemental Materials

Metrics

Downloaded 92 times

History

Received 2 October 2022

Accepted 4 April 2023

Published online 4 May 2023

Published in print June 2023

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/imt-2022-0250

Author contributions

M Noori, F Fayyaz and N Rezaei designed the study. M Noori and F Fayyaz performed the study selection and data extraction. M Noori conducted the analysis. M Noori and F Fayyaz wrote the first draft of the manuscript. M Noori, F Fayyaz and N Rezaei critically revised the manuscript. All authors reviewed the drafted manuscript for critical content and approved the final version of the manuscript.

Financial & competing interests disclosure

This study was supported by a grant from the Tehran University of Medical Sciences (grant no. 64964). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

PDF download