Publications

The Combination of MEK inhibitor with Immunomodulatory Antibodies Targeting PD-1 and PD-L1 Results in Prolonged Survival in Kras/p53-Driven Lung Cancer

Lee, J.W., Zhang, Y., Eoh, K.J. et al.

PURPOSE:
To characterize the tumor-infiltrating immune cells population in Kras/p53-driven lung tumors and to evaluate the combinatorial anti-tumor effect with MEK inhibitor (MEKi), trametinib, and immunomodulatory monoclonal antibodies (mAbs) targeting either programmed cell death protein-1 (PD-1) or programmed cell death protein ligand 1 (PD-L1) in vivo.

EXPERIMENTAL DESIGN:
Trp53FloxFlox;KrasG12D/+;Rosa26LSL-Luciferase/LSL-Luciferase (PKL) genetically engineered mice were utilized 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-PD1 or anti-PD-L1 mAbs synergistically increased anti-tumor 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.

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

Citation

Lee, J.W., Zhang, Y., Eoh, K.J. et al. "The Combination of MEK inhibitor with Immunomodulatory Antibodies Targeting PD-1 and PD-L1 Results in Prolonged Survival in Kras/p53-Driven Lung Cancer" Journal of Thoracic Oncology (2019): 1,046–60