Research progress on the effect of antibiotics and proton pump inhibitors on immunotherapy of lung cancer through intestinal flora_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

WANG Qi ^1,2,3 , SUN Fei ^1,2,3 , SHAN Yibo ^1,2,3 ,  SHI Hongcan ^1,2,3

1. Clinical Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, P. R. China;
2. Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, Jiangsu, P. R. China;
3. Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225009, Jiangsu, P. R. China;

Corresponding author：

SHI Hongcan, Email: shihongcan@yzu.edu.cn

Keywords：

Immmune checkpoint inhibitor; antibiotics; proton pump inhibitor; lung cancer; intestinal flora; review

DOI：

10.7507/1007-4848.202206024

Video：

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The treatment of patients with advanced lung cancer has been revolutionized with the advent of immunotherapy. However, not all patients can benefit equally from immunotherapy. In recent years, the relationship between intestinal flora and the efficacy of immunotherapy has gradually attracted scholars' attention. During the treatment of immune checkpoint inhibitors, the use of antibiotics, proton pump inhibitors and other drugs will affect the patient's intestinal flora, thus affecting the efficacy of immune checkpoint inhibitors, leading to poor prognosis of patients. This review will discuss that antibiotics and proton pump inhibitors reduce the efficacy of immunotherapy by affecting the diversity of intestinal flora, in order to facilitate the rational use of related drugs in clinical practice and improve the patient's outcomes.

Citation： WANG Qi, SUN Fei, SHAN Yibo, SHI Hongcan. Research progress on the effect of antibiotics and proton pump inhibitors on immunotherapy of lung cancer through intestinal flora. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2024, 31(3): 462-466. doi: 10.7507/1007-4848.202206024 Copy

1.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2.	Marx A, Chan JK, Coindre JM, et al. The 2015 World Health Organization classification of tumors of the thymus: Continuity and changes. J Thorac Oncol, 2015, 10(10): 1383-1395.
3.	Monteverdi S, Vita E, Sartori G, et al. Long-term survivors with immunotherapy in advanced NSCLC: Is 'cure' within reach? Transl Cancer Res, 2020, 9(2): 409-414.
4.	Qiu Z, Chen Z, Zhang C, et al. Achievements and futures of immune checkpoint inhibitors in non-small cell lung cancer. Exp Hematol Oncol, 2019, 8: 19.
5.	Yi M, Jiao D, Xu H, et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer, 2018, 17(1): 129.
6.	Chan TA, Yarchoan M, Jaffee E, et al. Development of tumor mutation burden as an immunotherapy biomarker: Utility for the oncology clinic. Ann Oncol, 2019, 30(1): 44-56.
7.	Viale G, Trapani D, Curigliano G. Mismatch repair deficiency as a predictive biomarker for immunotherapy efficacy. Biomed Res Int, 2017, 2017: 4719194.
8.	Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer, 2018, 118(1): 9-16.
9.	Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science, 2018, 359(6371): 97-103.
10.	Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science, 2018, 359(6371): 104-108.
11.	Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science, 2018, 359(6371): 91-97.
12.	Katayama Y, Yamada T, Shimamoto T, et al. The role of the gut microbiome on the efficacy of immune checkpoint inhibitors in Japanese responder patients with advanced non-small cell lung cancer. Transl Lung Cancer Res, 2019, 8(6): 847-853.
13.	Derosa L, Routy B, Thomas AM, et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer. Nat Med, 2022, 28(2): 315-324.
14.	Hakozaki T, Richard C, Elkrief A, et al. The gut microbiome associates with immune checkpoint inhibition outcomes in patients with advanced non-small cell lung cancer. Cancer Immunol Res, 2020, 8(10): 1243-1250.
15.	Ochi N, Ichihara E, Takigawa N, et al. The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression. Eur J Cancer, 2021, 149: 73-81.
16.	Tinsley N, Zhou C, Tan G, et al. Cumulative antibiotic use significantly decreases efficacy of checkpoint inhibitors in patients with advanced cancer. Oncologist, 2020, 25(1): 55-63.
17.	Kulkarni AA, Ebadi M, Zhang S, et al. Comparative analysis of antibiotic exposure association with clinical outcomes of chemotherapy versus immunotherapy across three tumour types. ESMO Open, 2020, 5(5): e000803.
18.	Santoni M, Piva F, Conti A, et al. Re: gut microbiome influences efficacy of pd-1-based immunotherapy against epithelial tumors. Eur Urol, 2018, 74(4): 521-522.
19.	Lu PH, Tsai TC, Chang JW, et al. Association of prior fluoroquinolone treatment with survival outcomes of immune checkpoint inhibitors in Asia. J Clin Pharm Ther, 2021, 46(2): 408-414.
20.	Stewardson AJ, Gaïa N, François P, et al. Collateral damage from oral ciprofloxacin versus nitrofurantoin in outpatients with urinary tract infections: A culture-free analysis of gut microbiota. Clin Microbiol Infect, 2015, 21(4): 344.e1-11.
21.	Rashid MU, Zaura E, Buijs MJ, et al. Determining the long-term effect of antibiotic administration on the human normal intestinal microbiota using culture and pyrosequencing methods. Clin Infect Dis, 2015, 60 Suppl 2: S77-S84.
22.	Pérez-Cobas AE, Artacho A, Knecht H, et al. Differential effects of antibiotic therapy on the structure and function of human gut microbiota. PLoS One, 2013, 8(11): e80201.
23.	Inagaki Y, Nakaya R, Chida T, et al. The effect of levofloxacin, an optically-active isomer of ofloxacin, on fecal microflora in human volunteers. Jpn J Antibiot, 1992, 45(3): 241-52.
24.	Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol, 2018, 29(6): 1437-1444.
25.	Kaderbhai C, Richard C, Fumet JD, et al. Antibiotic use does not appear to influence response to nivolumab. Anticancer Res, 2017, 37(6): 3195-3200.
26.	Hakozaki T, Okuma Y, Omori M, et al. Impact of prior antibiotic use on the efficacy of nivolumab for non-small cell lung cancer. Oncol Lett, 2019, 17(3): 2946-2952.
27.	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, 2019, 5(12): 1774-1778.
28.	Mielgo-Rubio X, Chara L, Sotelo-Lezama M, et al. Antibiotic use and PD-1 inhibitors: Shorter survival in lung cancer, especially when given intravenously. Type of infection also matters. J Thorac Oncol, 2018, 13(10): S389.
29.	Cortellini A, Di Maio M, Nigro O, et al. Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy. J Immunother Cancer, 2021, 9(4): e002421.
30.	Imhann F, Bonder MJ, Vich Vila A, et al. Proton pump inhibitors affect the gut microbiome. Gut, 2016, 65(5): 740-748.
31.	Freedberg DE, Lebwohl B, Abrams JA. The impact of proton pump inhibitors on the human gastrointestinal microbiome. Clin Lab Med, 2014, 34(4): 771-785.
32.	Kedika RR, Souza RF, Spechler SJ. Potential anti-inflammatory effects of proton pump inhibitors: A review and discussion of the clinical implications. Dig Dis Sci, 2009, 54(11): 2312-2317.
33.	Baek YH, Kang EJ, Hong S, et al. Survival outcomes of patients with nonsmall cell lung cancer concomitantly receiving proton pump inhibitors and immune checkpoint inhibitors. Int J Cancer, 2022, 150(8): 1291-1300.
34.	Qin BD, Jiao XD, Zhou XC, et al. Effects of concomitant proton pump inhibitor use on immune checkpoint inhibitor efficacy among patients with advanced cancer. Oncoimmunology, 2021, 10(1): 1929727.
35.	Liu C, Guo H, Mao H, et al. An up-to-date investigation into the correlation between proton pump inhibitor use and the clinical efficacy of immune checkpoint inhibitors in advanced solid cancers: A systematic review and meta-analysis. Front Oncol, 2022, 12: 753234.
36.	Chalabi M, Cardona A, Nagarkar DR, et al. Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: Pooled post hoc analyses of the OAK and POPLAR trials. Ann Oncol, 2020, 31(4): 525-531.
37.	Giordan Q, Salleron J, Vallance C, et al. Impact of antibiotics and proton pump inhibitors on efficacy and tolerance of anti-PD-1 immune checkpoint inhibitors. Front Immunol, 2021, 12: 716317.
38.	Samuelson DR, Welsh DA, Shellito JE. Regulation of lung immunity and host defense by the intestinal microbiota. Front Microbiol, 2015, 6: 1085.
39.	Costello EK, Lauber CL, Hamady M, et al. Bacterial community variation in human body habitats across space and time. Science, 2009, 326(5960): 1694-1697.
40.	Zitvogel L, Ma Y, Raoult D, et al. The microbiome in cancer immunotherapy: Diagnostic tools and therapeutic strategies. Science, 2018, 359(6382): 1366-1370.
41.	Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science, 2015, 350(6264): 1084-1089.
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, 2017, 28(6): 1368-1379.
43.	Bingula R, Filaire M, Radosevic-Robin N, et al. Desired turbulence? Gut-lung axis, immunity, and lung cancer. J Oncol, 2017, 2017: 5035371.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. Marx A, Chan JK, Coindre JM, et al. The 2015 World Health Organization classification of tumors of the thymus: Continuity and changes. J Thorac Oncol, 2015, 10(10): 1383-1395.
3. Monteverdi S, Vita E, Sartori G, et al. Long-term survivors with immunotherapy in advanced NSCLC: Is 'cure' within reach? Transl Cancer Res, 2020, 9(2): 409-414.
4. Qiu Z, Chen Z, Zhang C, et al. Achievements and futures of immune checkpoint inhibitors in non-small cell lung cancer. Exp Hematol Oncol, 2019, 8: 19.
5. Yi M, Jiao D, Xu H, et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer, 2018, 17(1): 129.
6. Chan TA, Yarchoan M, Jaffee E, et al. Development of tumor mutation burden as an immunotherapy biomarker: Utility for the oncology clinic. Ann Oncol, 2019, 30(1): 44-56.
7. Viale G, Trapani D, Curigliano G. Mismatch repair deficiency as a predictive biomarker for immunotherapy efficacy. Biomed Res Int, 2017, 2017: 4719194.
8. Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer, 2018, 118(1): 9-16.
9. Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science, 2018, 359(6371): 97-103.
10. Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science, 2018, 359(6371): 104-108.
11. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science, 2018, 359(6371): 91-97.
12. Katayama Y, Yamada T, Shimamoto T, et al. The role of the gut microbiome on the efficacy of immune checkpoint inhibitors in Japanese responder patients with advanced non-small cell lung cancer. Transl Lung Cancer Res, 2019, 8(6): 847-853.
13. Derosa L, Routy B, Thomas AM, et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer. Nat Med, 2022, 28(2): 315-324.
14. Hakozaki T, Richard C, Elkrief A, et al. The gut microbiome associates with immune checkpoint inhibition outcomes in patients with advanced non-small cell lung cancer. Cancer Immunol Res, 2020, 8(10): 1243-1250.
15. Ochi N, Ichihara E, Takigawa N, et al. The effects of antibiotics on the efficacy of immune checkpoint inhibitors in patients with non-small-cell lung cancer differ based on PD-L1 expression. Eur J Cancer, 2021, 149: 73-81.
16. Tinsley N, Zhou C, Tan G, et al. Cumulative antibiotic use significantly decreases efficacy of checkpoint inhibitors in patients with advanced cancer. Oncologist, 2020, 25(1): 55-63.
17. Kulkarni AA, Ebadi M, Zhang S, et al. Comparative analysis of antibiotic exposure association with clinical outcomes of chemotherapy versus immunotherapy across three tumour types. ESMO Open, 2020, 5(5): e000803.
18. Santoni M, Piva F, Conti A, et al. Re: gut microbiome influences efficacy of pd-1-based immunotherapy against epithelial tumors. Eur Urol, 2018, 74(4): 521-522.
19. Lu PH, Tsai TC, Chang JW, et al. Association of prior fluoroquinolone treatment with survival outcomes of immune checkpoint inhibitors in Asia. J Clin Pharm Ther, 2021, 46(2): 408-414.
20. Stewardson AJ, Gaïa N, François P, et al. Collateral damage from oral ciprofloxacin versus nitrofurantoin in outpatients with urinary tract infections: A culture-free analysis of gut microbiota. Clin Microbiol Infect, 2015, 21(4): 344.e1-11.
21. Rashid MU, Zaura E, Buijs MJ, et al. Determining the long-term effect of antibiotic administration on the human normal intestinal microbiota using culture and pyrosequencing methods. Clin Infect Dis, 2015, 60 Suppl 2: S77-S84.
22. Pérez-Cobas AE, Artacho A, Knecht H, et al. Differential effects of antibiotic therapy on the structure and function of human gut microbiota. PLoS One, 2013, 8(11): e80201.
23. Inagaki Y, Nakaya R, Chida T, et al. The effect of levofloxacin, an optically-active isomer of ofloxacin, on fecal microflora in human volunteers. Jpn J Antibiot, 1992, 45(3): 241-52.
24. Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol, 2018, 29(6): 1437-1444.
25. Kaderbhai C, Richard C, Fumet JD, et al. Antibiotic use does not appear to influence response to nivolumab. Anticancer Res, 2017, 37(6): 3195-3200.
26. Hakozaki T, Okuma Y, Omori M, et al. Impact of prior antibiotic use on the efficacy of nivolumab for non-small cell lung cancer. Oncol Lett, 2019, 17(3): 2946-2952.
27. 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, 2019, 5(12): 1774-1778.
28. Mielgo-Rubio X, Chara L, Sotelo-Lezama M, et al. Antibiotic use and PD-1 inhibitors: Shorter survival in lung cancer, especially when given intravenously. Type of infection also matters. J Thorac Oncol, 2018, 13(10): S389.
29. Cortellini A, Di Maio M, Nigro O, et al. Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy. J Immunother Cancer, 2021, 9(4): e002421.
30. Imhann F, Bonder MJ, Vich Vila A, et al. Proton pump inhibitors affect the gut microbiome. Gut, 2016, 65(5): 740-748.
31. Freedberg DE, Lebwohl B, Abrams JA. The impact of proton pump inhibitors on the human gastrointestinal microbiome. Clin Lab Med, 2014, 34(4): 771-785.
32. Kedika RR, Souza RF, Spechler SJ. Potential anti-inflammatory effects of proton pump inhibitors: A review and discussion of the clinical implications. Dig Dis Sci, 2009, 54(11): 2312-2317.
33. Baek YH, Kang EJ, Hong S, et al. Survival outcomes of patients with nonsmall cell lung cancer concomitantly receiving proton pump inhibitors and immune checkpoint inhibitors. Int J Cancer, 2022, 150(8): 1291-1300.
34. Qin BD, Jiao XD, Zhou XC, et al. Effects of concomitant proton pump inhibitor use on immune checkpoint inhibitor efficacy among patients with advanced cancer. Oncoimmunology, 2021, 10(1): 1929727.
35. Liu C, Guo H, Mao H, et al. An up-to-date investigation into the correlation between proton pump inhibitor use and the clinical efficacy of immune checkpoint inhibitors in advanced solid cancers: A systematic review and meta-analysis. Front Oncol, 2022, 12: 753234.
36. Chalabi M, Cardona A, Nagarkar DR, et al. Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: Pooled post hoc analyses of the OAK and POPLAR trials. Ann Oncol, 2020, 31(4): 525-531.
37. Giordan Q, Salleron J, Vallance C, et al. Impact of antibiotics and proton pump inhibitors on efficacy and tolerance of anti-PD-1 immune checkpoint inhibitors. Front Immunol, 2021, 12: 716317.
38. Samuelson DR, Welsh DA, Shellito JE. Regulation of lung immunity and host defense by the intestinal microbiota. Front Microbiol, 2015, 6: 1085.
39. Costello EK, Lauber CL, Hamady M, et al. Bacterial community variation in human body habitats across space and time. Science, 2009, 326(5960): 1694-1697.
40. Zitvogel L, Ma Y, Raoult D, et al. The microbiome in cancer immunotherapy: Diagnostic tools and therapeutic strategies. Science, 2018, 359(6382): 1366-1370.
41. Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science, 2015, 350(6264): 1084-1089.
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, 2017, 28(6): 1368-1379.
43. Bingula R, Filaire M, Radosevic-Robin N, et al. Desired turbulence? Gut-lung axis, immunity, and lung cancer. J Oncol, 2017, 2017: 5035371.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Research progress on the effect of antibiotics and proton pump inhibitors on immunotherapy of lung cancer through intestinal flora

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