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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma of Lung / drug therapy*
  • Adenocarcinoma of Lung / genetics*
  • Adenocarcinoma of Lung / immunology
  • Adenocarcinoma of Lung / pathology
  • Animals
  • Antineoplastic Agents, Immunological / administration & dosage
  • Antineoplastic Agents, Immunological / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • B7-H1 Antigen / biosynthesis
  • B7-H1 Antigen / immunology
  • Drug Synergism
  • Female
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Myeloid-Derived Suppressor Cells / immunology
  • Myeloid-Derived Suppressor Cells / pathology
  • Programmed Cell Death 1 Receptor / biosynthesis
  • Programmed Cell Death 1 Receptor / immunology
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Pyridones / pharmacology
  • Pyrimidinones / pharmacology
  • Survival Analysis
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • trametinib
  • MAP Kinase Kinase Kinases
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)