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Mitomycin C enhanced the efficacy of PD-L1 blockade in non-small cell lung cancer.

ABSTRACT: Programmed death ligand 1 (PD-L1) immune checkpoint inhibitors are promising therapeutic agents for treating cancers but the response rate is <20%. Some chemotherapeutic drugs could also activate an anticancer immune response to kill cancer cells, apart from their direct cytotoxicity. Our study investigated the combination of chemotherapeutic drugs with PD-L1 antibody to enhance the response rate of PD-L1 blockade. Non-small cell lung cancer (NSCLC) cells were pre-treated with mitomycin C (MMC) and then co-cultured with peripheral blood mononuclear cells (PBMCs) to investigate the effect of the combination of MMC with PD-L1 antibody. The drug combination was also evaluated in vivo in Lewis lung cancer (LLC) cells-bearing C57BL/6 mice. MMC increased the expressions of PD-L1 and MHC-I in NSCLC cells in vitro and in vivo and enhanced the cytotoxic effect of lymphocytes on NSCLC in vitro. In LLC-bearing mouse model, the combination of MMC and PD-L1 antibody was found to be more effective in retarding tumor growth and prolonging overall survival than either single treatment alone, which was associated with increased lymphocyte infiltration and granzyme B release. Mechanistically, MMC activated the ERK pathway, which subsequently enhanced the binding of c-JUN to the PD-L1 promoter and recruited its co-factor STAT3 to increase PD-L1 expression. The upregulated ERK pathway was shown to activate p65 to increase the MHC-I expression. MMC was shown to enhance the efficacy of PD-L1 blockade in NSCLC cells. Further study is warranted to translate the findings to clinical application.

SUBMITTER: Luo M

PROVIDER: S-EPMC7452895 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Mitomycin C enhanced the efficacy of PD-L1 blockade in non-small cell lung cancer.

Luo Min M Wang Fang F Zhang Hong H To Kenneth K W KKW Wu Shaocong S Chen Zhen Z Liang Shaobo S Fu Liwu L

Signal transduction and targeted therapy 20200828 1

Programmed death ligand 1 (PD-L1) immune checkpoint inhibitors are promising therapeutic agents for treating cancers but the response rate is <20%. Some chemotherapeutic drugs could also activate an anticancer immune response to kill cancer cells, apart from their direct cytotoxicity. Our study investigated the combination of chemotherapeutic drugs with PD-L1 antibody to enhance the response rate of PD-L1 blockade. Non-small cell lung cancer (NSCLC) cells were pre-treated with mitomycin C (MMC) ...[more]

PMID: 32855386

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Project description:Background:Cutaneous adverse events (AEs) have been positively associated with immune checkpoint inhibitor (ICI) efficacy in patients with melanoma, but little is known regarding the association between checkpoint inhibitor pneumonitis (CIP) and programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) inhibitor efficacy in non-small cell lung cancer (NSCLC). Methods:A single-institution, retrospective medical record review of patients with advanced or recurrent NSCLC who were treated with PD-1/PD-L1 inhibitors between 1 September 2015 and 1 June 2019 was conducted. A total of 276 NSCLC patients with or without immune-related pneumonitis who received at least one dose of ICIs and had at least one follow-up visit were identified. Kaplan-Meier curves of the progression-free survival (PFS) of patients stratified according to immune-related pneumonitis development were evaluated with the log-rank test as a preplanned primary objective. Multivariate analysis of PFS was performed with Cox proportional hazard regression models. Results:In the cohort of 276 patients, 42 patients developed CIP attributed to PD-1/PD-L1 inhibitors. Survival analysis showed that the overall response rate was significantly higher in patients with CIP than in those without CIP (61.90% versus 29.91%, respectively, p < 0.01), and that CIP development was significantly associated with increased PFS (45.80 weeks versus 21.15 weeks, respectively, p < 0.01). Additionally, 16-week landmark analysis produced the same results. Similarly, subgroup analysis of PD-1 inhibitor-treated, nivolumab-treated, and pembrolizumab-treated groups also revealed that CIP increased survival in NSCLC patients. Additionally, grade 1-2 pneumonitis showed an association with increased ICI efficacy in NSCLC; however, grade 3-4 pneumonitis did not. In addition, only two of the four pneumonitis radiological subtypes showed associations with increased ICI efficacy in NSCLC. Conclusion:CIP is associated with enhanced PD-1/PD-L1 inhibitor efficacy in NSCLC patients. Grade 1-2 pneumonitis and the radiological features of hypersensitivity and cryptogenic organizing pneumonia (COP) may be signs of enhanced ICI efficacy. However, further studies with larger numbers of patients and longer follow-up times are needed to validate our findings.

Project description:BackgroundProgrammed cell death ligand-1 (PD-L1) and ligand-2 (PD-L2) interaction with programmed cell death protein-1 (PD-1) represent an immune-inhibiting checkpoint mediating immune evasion and is, accordingly, an important target for blockade-based immunotherapy in cancer. In non-small-cell lung cancer (NSCLC), improved understanding of PD-1 checkpoint blockade-responsive biology and identification of biomarkers for prediction of a clinical response to immunotherapy is warranted. Thus, in the present study, we systematically described PD-L1 and PD-L2 expression correlated genes in NSCLC.MethodsWe performed comparative retrospective analyses to identify PD-L1 and PD-L2 mRNA expression correlated genes in NSCLC. For this, we examined available datasets from the cancer cell line encyclopedia (CCLE) project lung non-small-cell (Lung_NSC) and the cancer genome atlas (TCGA) projects lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC).ResultsAnalysis of the CCLE dataset Lung_NSC identified expression correlation between PD-L1 and PD-L2. Moreover, we identified expression correlation between 489 genes and PD-L1, 191 genes and PD-L2, and 111 genes for both. PD-L1 and PD-L2 also expression correlated in TCGA datasets LUAD and LUSC. In LUAD, we identified expression correlation between 257 genes and PD-L1, 914 genes and PD-L2, and 211 genes for both. In LUSC, we identified expression correlation between 26 genes and PD-L1, 326 genes and PD-L2, and 13 genes for both. Only a few genes expression correlated with PD-L1 and PD-L2 across the CCLE and TCGA datasets. Expression of Interferon signaling-involved genes converged in particular with the expression correlated genes for PD-L1 in Lung_NSC, for PD-L2 in LUSC, and for both PD-L1 and PD-L2 in LUAD. In LUSC, PD-L1, and to a lesser extent PD-L2, expression correlated with chromosome 9p24 localized genes, indicating a chromosome 9p24 topologically associated domain as an important driver of in particular LUSC PD-L1 expression. Expression correlation analyses of the PD-L1 and PD-L2 receptors programmed cell death protein-1 (PD-1), Cluster of differentiation 80 (CD80), and Repulsive guidance molecule B (RGMB) showed that PD-1 and CD80 expression correlated with both PD-L1 and PD-L2 in LUAD. CD80 expression correlated with PD-L2 in LUSC.ConclusionsWe present gene signatures associated with PD-L1 and PD-L2 mRNA expression in NSCLC which could possess importance in relation to understand PD-1 checkpoint blockade-responsive biology and development of gene signature based biomarkers for predicting clinical responses to immunotherapy.

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Mitomycin C enhanced the efficacy of PD-L1 blockade in non-small cell lung cancer.

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Mitomycin C enhanced the efficacy of PD-L1 blockade in non-small cell lung cancer.

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