Abstract 1718: Tumor immune gene profile before and after various targeted therapies in NSCLC PDXs
Authors: Elodie Montaudon, Sophie Vacher, Wilfrid Richer, Ahmed Dahmani, Caroline Guibaudet, Olivier Déas, Stefano Cairo, Ludmilla De Plater, Marine Dubois, Fariba Némati, Christine Sedlik, Jean-Gabriel Judde, Nicolas Girard, Ivan Bieche, Eliane Piaggio, Didier Decaudin
Journal: Cancer Research (2018)

Abstract Introduction: The blockade of immune checkpoints with antibodies directed against CTLA-4, PD-1 and PD-L1 molecules, is now entering in the current management of non-small cell lung cancer (NSCLC) patients; those tumors are heterogeneous regarding driver oncogenes, which predict the efficacy of targeted therapies (TT). In this context, our study aimed to define the relationship between conventional TT used in NSCLC and the dynamic expression of immune genes. Experimental procedure: Eight different NSCLC Patient-Derived Xenografts (PDXs) with defined mutations, were grafted in immunodeficient mice which were then treated by various TT (Table). About 3 tumors per group were collected at the end of the in vivo experiments. The expression of human and mouse genes, using species-specific primers was determined by qPCR and normalized to the expression of the human or mouse Total Binding Protein gene. Basal gene expression, predictive markers of response and resistance to tested therapies, as well as pharmacodynamics (PD) markers were analyzed. Results: Basal immune gene expression analysis revealed various immune profiles in this panel of NSCLC PDXs, with clustering of both models and genes. Predictive and pharmacodynamics markers underlined the impact of human HLA class I and II gene expression in the response to erlotinib and everolimus (HLA-A, HLA-DRA, and HLA-DRB); of B7-H3 (CD276), PDL1 (CD274) and Tigit (PVRIG) in the response to erlotinib; and of TNFSF7 (CD70) and TNFSF9 in the response to BKM120. PD markers showed that PDL1, B7-H3, and Tigit expression was highly impacted by everolimus, erlotinib, and BKM120 treatments, respectively. Complete gene expression results can be presented at the meeting. Conclusions: Using NSCLC PDXs, we have identified specific tumor immune profiles and a set of genes involved in the response to TT. Moreover, PD analysis of immune markers reveals potential combinations of TT with immune checkpoints blockade that may have important translational value. NSCLC PDXsLCF4LCF9LCF12LCF15LCF25LCF29ML1ML5HistologyAdenocarcinomaXXXXXXXLarge cellsXMUTATIONSEGFRXXKRASXXPi3KCAXXXTREATMENTS (Targets)Cetuximab (1)EGFRXXXXErlotinib (2)EGFRXXXXAfatinib (3)EGFR/HER2XXXXBKM120 (4)Pi3KXXXXXXXXEverolimus (5)mTORC1XXXXSelumetinib (6)MEK1/2XXXXXXXX1 + 2/XXXX1 + 3/XXXX1 + 4/X2 + 4/X3 + 4/X5 + 6/XXXX Citation Format: Elodie Montaudon, Sophie Vacher, Wilfrid Richer, Ahmed Dahmani, Caroline Guibaudet, Olivier Déas, Stefano Cairo, Ludmilla De Plater, Marine Dubois, Fariba Némati, Christine Sedlik, Jean-Gabriel Judde, Nicolas Girard, Ivan Bieche, Eliane Piaggio, Didier Decaudin. Tumor immune gene profile before and after various targeted therapies in NSCLC PDXs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1718.