00085472can143362-sup-141043_2_supp_3103672_nt3bl6.pptx (2.56 MB)

Supplementary Table and Supplementary Figures 1 through 6 from Control of PD-L1 Expression by Oncogenic Activation of the AKT–mTOR Pathway in Non–Small Cell Lung Cancer

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posted on 2023-03-30, 23:45 authored by Kristin J. Lastwika, Willie Wilson, Qing Kay Li, Jeffrey Norris, Haiying Xu, Sharon R. Ghazarian, Hiroshi Kitagawa, Shigeru Kawabata, Janis M. Taube, Sheng Yao, Linda N. Liu, Joell J. Gills, Phillip A. Dennis

Supplemental Table 1. Clinical and pathologic characteristics of patients included in tissue microarrays Supplementary Figure 1. B7-H4 expression is low in human and mouse lung cancer cell lines in vitro Supplementary Figure 2. B7-H1 expression does not change with MAPK or proliferation inhibition Supplementary Figure 3. Scoring of PD-L1 and pS6 staining in lung adenocarcinoma and squamous cell carcinoma TMAs Supplementary Figure 4. Co-expression of pS6 and PD-L1 staining in TMAs Supplemental Figure 5. The combination of rapamycin and anti-PD-1 antibody decreases KRAS-driven lung tumor growth Supplementary Figure 6. The combination of rapamycin and αPD-1 blockade decreases NNK-derived syngeneic lung tumor growth.

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ARTICLE ABSTRACT

Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT–mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNγ-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT–mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells. Cancer Res; 76(2); 227–38. ©2015 AACR.