DISSCUSSION
Although immune checkpoint inhibitors (ICIs) have soon yield unusually brilliant results in oncotherapy and become the forefront treatment against various advanced cancer, its efficacy is not universal and affected by a number of factors, for instance, the level of PD-L1 expression in tumor(35) and tumor mutation burden(TMB)(36). The gut microbiota diversity has been recognized to have significantly influence on effectiveness of ICIs treatment in recently years(4-7, 37). Numerous studies have shown that antibiotics (ATBs) have negative impact on PFS, OS and ORR of patients treated with ICIs(8-12). The molecular mechanisms below this phenomenon are not clear, the longstanding disturbance to the gut microbiota caused by ATBs might take the leading account(38).
Unlike the directly kill and bacteria growth suppression of ATBs, PPIs influence the diversity of gut microbiota by sophisticated ways (38, 39) and theoretically influence ICIs efficacy. Drug–drug interactions have significant effect in anti-cancer treatment, the combination of different classes of cytotoxic medications can improve the clinical benefit by overcoming drug resistance. Since the pharmacokinetic of ICIs is stable and lesser influenced by concomitant therapies(8), PPIs may affect the efficacy of ICIs through indirect ways. PPIs can exert immunosuppressive properties by reducing the expression of adhesion molecules and altering neutrophil response(40). Homicsko et al. conducted retrospectively analysis in Checkmate 069 clinical trial, a rise of leukocyte and neutrophil levels was detected and pro-inflammatory status was established in PPIs users before ICIs initiated thus interferes with treatment efficacy(41). Hence, the causality between PPI use and ICIs efficacy cannot be deduced directly from present study. Routy et al. found that NSCLC patients who benefit from ICIs therapy was associated with significantly higher abundance of Ruminococcus spp in feces(5). However, Jackson et al. found a significantly lower abundance of Ruminococcaceae family among PPIs users(15). Besides, dozens of microbiota species altered after PPIs use which can enhance or weaken anti‐PD‐1 therapy by multiple ways(15, 42), which further illustrate the complexity of PPIs influence on gut microbiota and eventually affect the therapeutic effect of ICIs. Therefore, it is still controversial about the impact of concomitant PPIs exposure on clinical outcome of cancer patients undergoing ICIs therapy due to limited literatures. Numerous basic researches are urgently needed to elucidate the cellular and molecular mechanisms between PPIs use and ICIs efficacy.
The early studies did not support the adverse influence of PPIs on PFS and OS among patients undergoing ICIs therapy(22, 32, 43, 44) probably due to small sample size. Nevertheless, with accumulation of evidence, the tendency of detrimental effect of concomitant PPIs exposure on outcome of ICIs therapy became increasingly apparent(12, 25, 28, 30, 31, 33). It is worth mentioning that data from 4 randomized controlled trial were extracted retrospectively. The POPLAR and OAK trials explored the PFS and OS of PPIs use in NSCLC patients treated with atezolizumab(12),the result showed that PPIs users had poor outcome and PPIs exposure may affect the efficacy of atezolizumab. The IMvigor210 and IMvigor211 were conducted in advanced urothelial cancer patients undergoing atezolizumab treatment, their analysis indicated that PPIs users had significantly shorter PFS and OS(33).
Our meta-analysis consists of 14 studies including 6716 cancer patients receiving ICIs therapy indicated that concomitant PPIs exposure was significantly related to shorter OS and PFS, the pooled HR for OS and PFS were 1.388(95%CI:1.278-1.498, P<0.001) and 1.285(95%CI:1.193-1.384, P<0.001), respectively. PPIs are becoming one of the most frequently inappropriate prescribed and abused agents worldwide among cancer and other patients(45-48), and our findings raise concerns about PPIs use especially in cancer patients receiving ICIs therapy and remind of clinician be cautious of PPIs delivery during ICIs treatment. However, there are several drawbacks in our study, too. Firstly, all the included studies are retrospective and we did detect publication bias in this analysis. Secondly, there are no enough data to conduct subgroup analysis. The type of PPIs and dosage, ICIs type, cancer type, ICIs alone or in combination with others were variables and not all of them were homogeneous in every study, which demanded large randomized controlled clinical trials to validate the conclusion. Thirdly, we noticed that gastrointestinal cancer studies are not available in this study, most of the studies were concentrated on NSCLC and melanoma, which made the results to be limited. Further researches are needed to delve into the relationship between PPIs exposure and ICIs efficacy among gastrointestinal cancer patients.
Collectively, our findings indicate that concomitant PPIs exposure is significantly associated with shorter OS and PFS among patients undergoing ICIs therapy. Further randomized controlled trials are needed to confirm the findings. Clinical oncologists must take the detrimental effect of PPIs use into account when ICIs are given.
Conflict of Interest
The authors declare that the study was performed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.