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A study of PD-L1 expression in KRAS mutant non-small cell lung cancer cell lines exposed to relevant targeted treatments.

ABSTRACT: We investigated PD-L1 changes in response to MEK and AKT inhibitors in KRAS mutant lung adenocarcinoma (adeno-NSCLC). PD-L1 expression was quantified using immunofluorescence and co-culture with a jurkat cell-line transfected with NFAT-luciferase was used to study if changes in PD-L1 expression in cancer cell lines were functionally relevant. Five KRAS mutant cell lines with high PD-L1 expression (H441, H2291, H23, H2030 and A549) were exposed to GI50 inhibitor concentrations of a MEK inhibitor (trametinib) and an AKT inhibitor (AZD5363) for 3 weeks. Only 3/5 (H23, H2030 and A549) and 2/5 cell lines (H441 and H23) showed functionally significant increases in PD-L1 expression when exposed to trametinib or AZD5363 respectively. PD-L1 overexpression is not consistent and is unlikely to be an early mechanism of resistance to KRAS mutant adeno-NSCLC treated with MEK or AKT inhibitors.

SUBMITTER: Minchom A

PROVIDER: S-EPMC5628934 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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A study of PD-L1 expression in KRAS mutant non-small cell lung cancer cell lines exposed to relevant targeted treatments.

Minchom Anna A Thavasu Parames P Ahmad Zai Z Stewart Adam A Georgiou Alexandros A O'Brien Mary E R MER Popat Sanjay S Bhosle Jaishree J Yap Timothy A TA de Bono Johann J Banerji Udai U

PloS one 20171005 10

We investigated PD-L1 changes in response to MEK and AKT inhibitors in KRAS mutant lung adenocarcinoma (adeno-NSCLC). PD-L1 expression was quantified using immunofluorescence and co-culture with a jurkat cell-line transfected with NFAT-luciferase was used to study if changes in PD-L1 expression in cancer cell lines were functionally relevant. Five KRAS mutant cell lines with high PD-L1 expression (H441, H2291, H23, H2030 and A549) were exposed to GI50 inhibitor concentrations of a MEK inhibitor ...[more]

PMID: 28982179

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Project description:Non-small cell lung cancer (NSCLC) patients harboring a KRAS mutation have unfavorable therapeutic outcomes with chemotherapies, and the mutation also renders tolerance to immunotherapies. There is an unmet need for a new strategy for overcoming immunosuppression in KRAS-mutant NSCLC. The recently discovered role of melatonin demonstrates a wide spectrum of anticancer impacts; however, the effect of melatonin on modulating tumor immunity is largely unknown. In the present study, melatonin treatment significantly reduced cell viability accompanied by inducing cell apoptosis in KRAS-mutant NSCLC cell lines including A549, H460, and LLC1 cells. Mechanistically, we found that lung cancer cells harboring the KRAS mutation exhibited a higher level of programmed death ligand 1 (PD-L1). However, treatment with melatonin substantially downregulated PD-L1 expressions in both the presence and absence of interferon (IFN)-γ stimulation. Moreover, KRAS-mutant lung cancer cells exhibited higher Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) levels, and PD-L1 expression was positively correlated with YAP and TAZ in lung cancer cells. Treatment with melatonin effectively suppressed YAP and TAZ, which was accompanied by downregulation of YAP/TAZ downstream gene expressions. The combination of melatonin and an inhibitor of YAP/TAZ robustly decreased YAP and PD-L1 expressions. Clinical analysis using public databases revealed that PD-L1 expression was positively correlated with YAP and TAZ in patients with lung cancer, and PD-L1 overexpression suggested poor survival probability. An animal study further revealed that administration of melatonin significantly inhibited tumor growth and modulated tumor immunity in a syngeneic mouse model. Together, our data revealed a novel antitumor mechanism of melatonin in modulating the immunosuppressive tumor microenvironment by suppressing the YAP/PD-L1 axis and suggest the therapeutic potential of melatonin for treating NSCLC.

Project description:BackgroundKRAS (Kirsten rat sarcoma viral oncogene homolog) gene mutation is one of the common driver gene mutations in non-small cell lung cancer (NSCLC) with poor prognosis. There are limited effective treatments for advanced NSCLC patients with KRAS mutation. This study aimed to evaluate the effectiveness of PD-1/L1 immune checkpoint inhibitors (ICIs) as a first-line immunotherapy for advanced NSCLC patients harboring KRAS oncogene mutation.MethodsThis multicenter retrospective real-world study was conducted from 2019 to 2024 at Shanghai Changzheng Hospital and Shanghai Municipal Hospital of Traditional Chinese Medicine, including 78 patients who received immunotherapy using PD-1/L1 ICIs, and 29 patients who received traditional platinum-doublet chemotherapy. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints included the objective response rate (ORR), disease control rate (DCR), and correlation of prognostic biomarkers with survival outcomes.ResultsNo significant difference in ORR and DCR was observed between the two groups. The median PFS in immunotherapy group was longer than that in chemotherapy group [7.9 months (95% CI: 5.3-10.5) vs. 6.0 months (95% CI: 3.8-8.2), P = 0.030], and there was no significant difference in OS between the two groups (16.2 vs. 19.2 months, P > 0.05). Multivariate analysis identified PD-L1 expression as an independent protective factor for PFS (HR = 0.397, 95% CI: 0.178-0.887, P = 0.024), and elevated CRP (HR = 1.005, 95% CI: 1.001-1.010, P = 0.022), CEA (HR = 1.008, 95% CI: 1.001-1.014, P = 0.030) and neutrophil-to-lymphocyte ratio (NLR) (HR = 1.105, 95% CI: 1.024-1.193, P = 0.010) were independent risk factors for progression.ConclusionThe first-line treatment with PD-1/PD-L1 ICIs showed numerically better clinical efficacy than the traditional double-agent chemotherapy in patients with KRAS-mutated NSCLC, especially in PFS. Additionally, PD-L1 expression, C reactive protein, CEA, and NLR could serve as markers for predicting the efficacy of immunotherapy in patients with KRAS-mutated NSCLC.

Project description:Although programmed cell death-1/programmed death-ligand 1 (PD-L1) inhibitors show remarkable antitumor activity, a large portion of patients with cancer, even those with high PD-L1-expressing tumors, do not respond to their effects. Most PD-L1 inhibitors contain modified fragment crystallizable region (Fc) receptor binding sites to prevent antibody-dependent cellular cytotoxicity (ADCC) against PD-L1-expressing non-tumor cells. However, natural killer (NK) cells have specific antitumor activity in the presence of tumor-targeting antibody through ADCC, which could enhance NK cell-induced cytotoxicity. We evaluated the antitumor efficacy of ADCC via anti-PD-L1 monoclonal antibodies (mAbs) and NK cells against several PD-L1-positive cancer cell lines. Various cancer cell lines were used as target cell lines. Surface PD-L1 expression was analyzed by flow cytometry. IMC-001 and anti-hPD-L1-hIgG1 were tested as anti-PD-L1 mAbs with ADCC and atezolizumab as an anti-PD-L1 mAb without ADCC. NK cell cytotoxicity was measured by 51Cr-release assay and CD107a degranulation assay. Also, live cell imaging was performed to evaluate cytotoxicity in a single-cell level. NK-92-CD16 (CD16-transduced NK-92 cell line) and peripheral blood mononuclear cells from healthy donors, respectively, were used as an effector cell. FcγRIIIa (CD16a)-V158F genotyping was performed for healthy donors. We demonstrated that the cytotoxicity of NK-92-CD16 cells toward PD-L1-positive cancer cell lines was significantly enhanced in the presence of anti-PD-L1 mAb with ADCC. We also noted a significant increase in primary human NK cell cytotoxicity against PD-L1-positive human cancer cells when cocultured with anti-PD-L1 mAb with ADCC. Moreover, NK cells expressing a FCGR3A high-affinity genotype displayed higher anti-PD-L1 mAb-mediated ADCC lysis of tumor cells than donors with a low-affinity genotype. These results suggest that NK cells induce an ADCC response in combination with anti-PD-L1 mAbs, which helps promote ADCC antitumor activity against PD-L1-positive tumors. This study provides support for NK cell immunotherapy against high PD-L1-expressing tumors in combination with ADCC through anti-PD-L1 mAbs.

Dataset Information

A study of PD-L1 expression in KRAS mutant non-small cell lung cancer cell lines exposed to relevant targeted treatments.

Publications

A study of PD-L1 expression in KRAS mutant non-small cell lung cancer cell lines exposed to relevant targeted treatments.

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