| First Author | Lee JW | Year | 2019 |
| Journal | J Thorac Oncol | Volume | 14 |
| Issue | 6 | Pages | 1046-1060 |
| PubMed ID | 30771521 | Mgi Jnum | J:349051 |
| Mgi Id | MGI:7646011 | Doi | 10.1016/j.jtho.2019.02.004 |
| Citation | Lee JW, et al. (2019) 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 14(6):1046-1060 |
| abstractText | 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: Trp53(FloxFlox);Kras(G12D/+);Rosa26(LSL-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-1(high) MDSCs, in particular, Ly6G(high) 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. |
