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.