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J Thorac Oncol. 2019 Jun;14(6):1046-1060. doi: 10.1016/j.jtho.2019.02.004. Epub 2019 Feb 13.

The Combination of MEK Inhibitor With Immunomodulatory Antibodies Targeting Programmed Death 1 and Programmed Death Ligand 1 Results in Prolonged Survival in Kras/p53-Driven Lung Cancer.

Author information

1
Section of Medical Oncology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut.
2
Department of Immunobiology, Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut.
3
Section of Medical Oncology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut; Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul, South Korea.
4
Department of Internal Medicine, Chungnam National University Hospital, Daejeon, South Korea.
5
Department of Immunobiology and Molecular, Cellular and Developmental Biology, Yale School of Medicine, New Haven, Connecticut.
6
Department of Thoracic, Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas.
7
Section of Medical Oncology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut; Developmental Therapeutics Translational Research Program, Yale Comprehensive Cancer Center, New Haven, Connecticut. Electronic address: jpeter.koo@yale.edu.

Abstract

INTRODUCTION:

This study aimed to characterize the tumor-infiltrating immune cells population in Kras/tumor protein 53 (Trp53)-driven lung tumors and to evaluate the combinatorial antitumor effect with MEK inhibitor (MEKi), trametinib, and immunomodulatory monoclonal antibodies (mAbs) targeting either programmed death -1 (PD-1) or programmed cell death ligand 1 (PD-L1) in vivo.

METHODS:

Trp53FloxFlox;KrasG12D/+;Rosa26LSL-Luciferase/LSL-Luciferase (PKL) genetically engineered mice were used to develop autochthonous lung tumors with intratracheal delivery of adenoviral Cre recombinase. Using these tumor-bearing lungs, tumor-infiltrating immune cells were characterized by both mass cytometry and flow cytometry. PKL-mediated immunocompetent syngeneic and transgenic lung cancer mouse models were treated with MEKi alone as well as in combination with either anti-PD-1 or anti-PD-L1 mAbs. Tumor growth and survival outcome were assessed. Finally, immune cell populations within spleens and tumors were evaluated by flow cytometry and immunohistochemistry.

RESULTS:

Myeloid-derived suppressor cells (MDSCs) were significantly augmented in PKL-driven lung tumors compared to normal lungs of tumor-free mice. PD-L1 expression appeared to be highly positive in both lung tumor cells and, particularly MDSCs. The combinatory administration of MEKi with either anti-PD-1 or anti-PD-L1 mAbs synergistically increased antitumor response and survival outcome compared with single-agent therapy in both the PKL-mediated syngeneic and transgenic lung cancer models. Theses combinational treatments resulted in significant increases of tumor-infiltrating CD8+ and CD4+ T cells, whereas attenuation of CD11b+/Gr-1high MDSCs, in particular, Ly6Ghigh polymorphonuclear-MDSCs in the syngeneic model.

CONCLUSIONS:

These findings suggest a potential therapeutic approach for untargetable Kras/p53-driven lung cancers with synergy between targeted therapy using MEKi and immunotherapies.

KEYWORDS:

Kras/p53-driven lung cancer; Myeloid-derived suppressor cells; Programmed death 1; Programmed death ligand 1; Trametinib

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