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

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d1550050e251">Purpose:</h5> <p id="P1">To characterize the tumor-infiltrating immune cells population in <i>Kras/p53-driven</i> 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) <i>in vivo.</i> </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d1550050e262">Experimental Design:</h5> <p id="P2"> <i>Trp53</i> ^{<i>FloxFlox</i>} <i>;Kras</i> ^{<i>G12D/+</i>} <i>;Rosa26</i> ^{<i>LSL-Luciferase/LSL-Luciferase</i>} (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. <i>PKL</i>-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. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d1550050e298">Results:</h5> <p id="P3">Myeloid-derived suppressor cells (MDSCs) were significantly augmented in <i>PKL</i>-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 <i>PKL</i>-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. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d1550050e325">Conclusion:</h5> <p id="P4">These findings suggest a potential therapeutic approach for untargetable <i>Kras/p53-</i>driven lung cancers with synergy between targeted therapy using MEKi and immunotherapies. </p> </div>