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

Abstract

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.

Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance inKRAS/p53mutant lung cancers

“…Consistent with previous work 30,33 , MAPK inhibition in combination with PD-L1 blockade demonstrated an initial reduction in KP lung tumor growth. However, despite the initial response to the double combination therapy and even anti-PD-L1 monotherapy in our KP pre-clinical GEMMs, lung tumors eventually developed resistance to combination therapy.…”

“…Here we identified a reciprocal expression between PD-L1 and MAPK signaling when lung tumors were treated with MEK inhibitor or anti-PD-L1, respectively, validating a promising dual combinatorial therapy approach previously reported in multiple cancer types 28,29,30,31,32 .…”

Myeloid-derived suppressor cells—new and exciting players in lung cancer

“…(1) enhancing T cell infiltration both in the tumor microenvironment and inside the tumor bed, (2) decreasing the number of PMN-MDSCs in the tumor, and (3) suppressing tumor cell proliferation and leading to apoptosis in tumor cells [106].…”

Upregulation of secreted phosphoprotein 1 affects malignant progression, prognosis, and resistance to cetuximab via the KRAS/MEK pathway in head and neck cancer

“…25 Combination of MEK inhibitor with immunotherapies can prolong the survival in KRAS/p53-driven lung cancer. 44 Unlike in colorectal and lung cancers, the treatment regimen for HNSCC patients is not determined on the basis of molecular determinants of responses. 45 In the present study, we explored the molecular mechanism of resistance to cetuximab in HNSCC.…”