The association between antibiotic use and outcomes of HCC patients treated with immune checkpoint inhibitors

Abstract

ObjectiveRecently, immune checkpoint inhibitor (ICI) treatment has shown encouraging performance in improving the prognosis of hepatocellular carcinoma (HCC) patients. The gut microbiome plays a vital role in altering the efficacy of ICIs, which may be impacted by antibiotics. The aim of the meta-analysis is to estimate the influence of antibiotic use on the survival of HCC patients treated with ICIs.MethodsThe literature review was conducted using databases like PubMed, EMBASE, Cochrane Library, CNKI, WANFANG DATA, VIP, Google Scholar, and ClinicalTrials.gov before May 15, 2022. The primary endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR).ResultsA total of six retrospective studies met the inclusion criteria. 1056 patients were included in the study, of which 352 (33.33%) received antibiotic treatment. The meta-analysis results revealed antibiotic use did not affect the OS (HR: 1.41, 95% CI: 0.96-2.08, P = 0.088) and PFS (HR: 1.21, 95% CI: 0.73-2.00, P = 0.459) in HCC patients treated with ICIs. Besides, the use of antibiotics did not reduce the ORR (OR: 1.06, 95% CI: 0.69-1.64, P = 0.784) and DCR (OR: 0.42, 95% CI: 0.09-2.06, P = 0.286) in HCC patients treated with ICIs.ConclusionCurrent evidence reveals that antibiotic use does alter the therapeutic efficacy of ICIs in HCC patients.Systematic Review Registrationhttps://www.crd.york.ac.uk/, identifier CRD42022311948.

A systematic review and meta-analysis evaluating the impact of antibiotic use on the clinical outcomes of cancer patients treated with immune checkpoint inhibitors

“…confirmed the reliability and the robustness of the results, and which is in accordance with the meta-analyses previously published on the subject (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Exclusion of cohorts not having performed multivariate analyses further showed that this suggested deleterious impact persisted despite adjustment for confounding factors, suggesting that ABX use is an independent predictor factor for OS and PFS.…”

“…With the increasing use of immune checkpoint inhibitors in cancer care, considerable efforts have been made to identify factors that may alter their effectiveness, and ABX use has recently emerged as one of them, as demonstrated by numerous retrospective and prospective studies (7,(12)(13)(14) and several meta-analyses (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) published on the topic. Our meta-analysis stands out from the others in that it included more than three-fold the number of Forest plot of odds ratios of the progressive disease rate of patients diagnosed with cancer and exposed to antibiotics versus not exposed to antibiotics around immune checkpoint inhibitor treatment initiation.…”

“…ABX exposure was notably shown in numerous retrospective and prospective studies to adversely influence the clinical outcomes of patients suffering from different types of cancer treated with ICIs (12-14). Sixteen meta-analyses were published on the subject and consistently concluded on a damaging impact of ABX use on the clinical outcomes of cancer patients treated with ICIs (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), yet only 48 cohorts (12,794 patients) were included in the most comprehensive meta-analysis (23), leaving a large part of the literature unexploited.…”

Identification of an immune-related 6-lncRNA panel with a good performance for prognostic prediction in hepatocellular carcinoma by integrated bioinformatics analysis

“…[36,37] By checking the immune characteristics of HCC patients, that is the molecular and cellular characterization of TIME, individualized risk stratification of HCC patients can be achieved, and patients with significant therapeutic effects on immunotherapy can be identified, thereby guiding clinical decision-making and realizing the purpose of precise treatment. [38–40] In the present study, our 6-lncRNA panel demonstrated excellent stratification ability for immune infiltrating cells such as natural regulatory T cells, B cells, follicular helper T cells, mucosal-associated invariant T, macrophages and NK cells from HCC patients. These immune-infiltrating cells have all been found to be biomarkers for the prognosis of HCC, [41–47] which was of great significance for further research on the immune mechanism of HCC and the development of new diagnostic and therapeutic approaches.…”

Endotoxemia and Gastrointestinal Cancers: Insight into the Mechanisms Underlying a Dangerous Relationship

“…Antibiotic treatment also decreases intestinal LPS overload [ 157 ]; in murine models of colitis-associated CRC, antibiotics and the TLR-4-blocking molecule Resatorvid [ 158 ] are able to inhibit inflammation, decreasing TLR-4 signaling and TLR-4+ tumor-infiltrating macrophages [ 159 ]. However, in a mouse model of methionine/choline-diet-induced NASH, antibiotics administration was reported to have negative effects [ 160 ], and a negative impact on HCC immunotherapy is described in different studies [ 161 , 162 , 163 ], so further evidence is needed to elucidate the role of antibiotics in gut microbiota modulation and tumor development. TLR-4 inhibition of host anti-tumor activity is also controversial, because, if it is true that tumor progression involves TLR-4-mediated production of pro-inflammatory and immunosuppressive cytokines, TLR-4 antagonists reduce pro-inflammatory response, but also compromise host immunity [ 164 ].…”