Antibiotics are associated with attenuated efficacy of anti-PD-1/PD-L1 therapies in Chinese patients with advanced non-small cell lung cancer

Zhao, Sha; Gao, Guanghui; Li, Wei; Li, Xuefei; Zhao, Chao; Jiang, Tao; Jia, Yijun; He, Yayi; Li, Aiwu; Su, Chunxia; Ren, Shengxiang; Chen, Xiaoxia; Zhou, Caicun

doi:10.1016/j.lungcan.2019.01.017

Cited by 136 publications

(124 citation statements)

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“…Soft tissue infections or deep neck infection in the head and neck region can occur in patients with locally advanced HNSCC. Antibiotic usage around the time of ICI treatment could dampen the effects of PD-1/PD-L1 blockade (36)(37)(38)(39), as antibiotics usage for head and neck soft tissue infection will disrupt the integrity of the gut microbiome. A recent study demonstrates that disruptions in the gut microbiome composition, also known as dysbiosis, is one of the mechanisms of primary resistance to ICI therapy (36).…”

Section: Primary Resistance To Icis In Hnsccmentioning

confidence: 99%

Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer

Kok

2020

Front. Oncol.

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Starting in 2014, large phase III clinical trials began to disclose the study results of using programmed death (PD)-1 immune checkpoint inhibitors (ICIs) (pembrolizumab, nivolumab) and PD-ligand (L)1 (atezolizumab, durvalumab, avelumab) ICIs immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). In the recurrent and metastatic (R/M), cisplatin-refractory setting, nivolumab achieved a 2.2-fold increase of the median 1-year overall survival as compared with investigators' choice of salvage chemotherapy (36.0 vs. 16.6%). A paradigm shift to the winning regimen, pembrolizumab combined with platinum and infusional fluorouracil, has outperformed the past gold standard of cetuximab-based platinum and fluorouracil combination in terms of overall survival (median, 13.6 vs. 10.1 mo) when administered as the first-line treatment for R/M HNSCC. Nevertheless, many patients still did not respond to the PD-1/PD-L1 checkpoint inhibitor treatment, indicating innate, adapted, or quickly acquired resistance to the immunotherapy. The mechanisms of resistance to ICIs targeting the PD-1/PD-L1 signaling pathway in the context of HNSCC are the focus of this review. The past 5 years have seen improved understanding of the mechanisms underlying checkpoint inhibition resistance in tumor cells, such as: tumor cell adaption with malfunction of the antigen-presenting machinery via class I human leukocyte antigen (HLA), reintroduction of cyclin D-cyclin-dependent kinase (CDK) 4 complex to cell cycles, enrichment of CD44+ cancer stem-like cells, or development of inactivating mutation in IKZF1 gene; impairment of T-cell functions and proliferation through mutations in the interferon-γ-regulating genes, suppression of the stimulator of interferon genes (STING) pathway, or resulted from constitutional nutritional iron deficiency state; metabolic reprogramming by cancer cells with changes in metabolites such as GTP cyclohydrolase 1, tetrahydrobiopterin, kynurenine, indoleamine 2,3-dioxygenase, and arginase 1; defective dendritic cells, CD-69 sufficient state; and the upregulation or activation of the alternative immune checkpoints, including lymphocyte activation gene-3 (LAG3), T-cell Kok Immune Evasion From PD-1/PD-L1 Immunotherapy immunoglobulin and ITIM domain (TIGIT)/CD155 pathway, T-cell immunoglobulin mucin-3 (TIM-3), and V domain-containing Ig suppressor of T-cell activation (VISTA). Several potential biomarkers or biosignatures, which could predict the response or resistance to the PD-1/PD-L1 checkpoint immunotherapy, are also discussed.

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Section: Primary Resistance To Icis In Hnsccmentioning

confidence: 99%

Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer

Kok

2020

Front. Oncol.

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“…Among the publications retrieved using electronic search, 15 studies were eligible for quantitative analysis, for a total of 2,363 patients [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

Survival of Patients Treated with Antibiotics and Immunotherapy for Cancer: A Systematic Review and Meta-Analysis

Petrelli

Iaculli²,

Signorelli

et al. 2020

Preprint

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Antibiotics (ABs) are common medications used for treating infections. In cancer patients treated with immune checkpoint inhibitors (ICIs), concomitant exposure to ABs may impair the efficacy of ICIs and lead to a poorer outcome compared to AB non-users. We report here the results of a meta-analysis evaluating the effects of ABs on the outcome of patients with solid tumors treated with ICIs. PubMed, the Cochrane Library, and Embase were searched from inception until September 2019 for observational or prospective studies reporting prognosis of adult patients with cancer treated with ICIs and with or without ABs. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The effect size was reported as hazard ratios (HRs) with a 95% confidence interval (CI), and an HR > 1 associated with a worse outcome in ABs users compared to no-ABs users. Fifteen publications were retrieved for a total of 2363 patients. In the main analysis (n = 15 studies reporting data), OS was reduced in patients exposed to ABs before or during treatment with ICIs (HR = 2.07, 95%CI 1.51–2.84; P<.01). Similarly, PFS was inferior in ABs users in n = 13 studies with data available (HR = 1.53, 95%CI 1.22–1.93; p<.01). In cancer patients treated with ICIs, AB use significantly reduces OS and PFS. Short duration/course of ABs may be considered in clinical situations in which they are strictly needed.

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“…These decreases are explained at least partly by the higher PD rate in the ATB group. Almost 10% of patients with cancer undergoing chemotherapy require ATB treatment due to the immunosuppressive nature of malignancies and lymphodepletion induced by anticancer therapies (8,9). Recent studies support the viewpoint that the microbiota regulates the e cacy of anticancer therapy and that the corresponding microbiota targeting may change the drug e cacy (10).…”

Section: Discussionmentioning

confidence: 99%

Negative association between antibiotics and clinical activity in patients with advanced gastric cancer

Zhang

Jin

Jing

et al. 2020

Preprint

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Background Antibiotics (ATBs) induce dysbiosis of the gut microbiota by altering the diversity and composition of the microbiota, which mediates the efficacy and toxicity of cancer therapy. The influence of dysbiosis induced by ATB administration on primary resistance to chemotherapy in patients with advanced gastric cancer (GC) has rarely studied. We evaluated the effect of ATB administration on chemotherapy efficacy in patients with advanced GC. Methods Patients with GC were divided into two groups according to the statues of ATB administration: ATB-treated and control groups. Tumor responses, progression-free survival (PFS), and overall survival (OS) were assessed. Results We found that the incidence of progressive disease in the ATB-treated group was significantly higher when compared with that in the control group that received no ATB treatment (72.73% vs. 29.55%, p = 0.007). In addition, ATB administration was associated with shorter PFS [median PFS: 1.47 vs. 4.97 months, hazard ratio (HR): 2.296, 95% confidence interval (CI): 1.214–4.342, p = 0.011] and reduced OS (median OS: 9.97 vs. 13.3 months, HR: 2.101, 95% CI: 1.030–4.286, p = 0.041) based on univariate analysis. Subsequent multivariate analysis also indicated that ATB administration was an independent prognostic factor for PFS (HR: 3.361, 95% CI: 1.592–7.097, p = 0.001) and OS (HR: 2.280, 95% CI: 1.042–4.991, p = 0.039). Conclusions ATB administration is associated with reduced chemotherapy efficacy and poor prognosis in patients with advanced GC. Modulations in ATB-related dysbiosis and gut microbiota composition improve the clinical outcomes of chemotherapy.

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Antibiotics are associated with attenuated efficacy of anti-PD-1/PD-L1 therapies in Chinese patients with advanced non-small cell lung cancer

Cited by 136 publications

References 47 publications

Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer

Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer

Survival of Patients Treated with Antibiotics and Immunotherapy for Cancer: A Systematic Review and Meta-Analysis

Negative association between antibiotics and clinical activity in patients with advanced gastric cancer

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