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