Abstract 1007: Durvalumab + tremelimumab increase T cells and decrease expression of genes involved in angiogenesis, EMT, and the Th2 pathway in the NSCLC tumor microenvironment

Abstract

Abstract Background Cancer cells utilize multiple mechanisms to suppress the development of an effective anti-tumor immune response. Overcoming these suppressive mechanisms to restore effector function to exhausted tumor infiltrating lymphocytes (TILs) is critical for response to checkpoint blockade; however, the specific changes associated with different IO treatments has yet to be fully characterized. We treated NSCLC tumor fragments or digests ex vivo with the anti-PD-L1 antibody durvalumab (D) alone or in combination with the anti-CTLA-4 antibody tremelimumab (T) to explore changes in gene and protein expression associated with checkpoint blockade. Methods 10 NSCLC tumors (5 fresh and 5 frozen) were analyzed. Minced fresh tumor fragments or frozen tumor digests were seeded in media containing low dose interleukin-2 (IL-2) plus D and/or T or the appropriate isotype controls. After 1-2 weeks of treatment, TILs were evaluated for changes in cytokine production, as well as the expression of inhibitory receptors and other immune-related markers. Microarray gene expression analysis was performed on a subset (n = 2) of the NSCLC tumors evaluated. Results Of 10 NSCLC tumors tested, 4 showed a robust increase in IFNg production (> 2-fold) relative to isotype controls in both D and D + T treated conditions, with an additional 3 tumors showing smaller, but consistent 30-40% increases in IFNg production. 4 NSCLC tumors showed at least a 30% increase in CD4+ and CD8+ T cell proliferation following D and D+T, with a maximum increase of 120% in CD4+ T cells due to D+T. D and D+T reduced expression of the Th2 pathway genes IL-4, IL-5, and IL-9 (2-8 fold compared to isotype control) and > 2-fold increased expression of THEMIS and CXCL13, genes important for TCR signaling and T follicular helper cell mediated B cell recruitment, respectively. D + T treatment resulted in greater reduction compared to D in expression of genes involved in regulating angiogenesis (VHL, FGD5; > 2-fold), as well as metastasis (PFTK1; 2.2-fold), epithelial to mesenchymal transition (EMT) (CD133; 2-fold), and T reg function (TGFB2 and IL17RB; 1.8-2-fold). Conclusions Our results demonstrate that D + T augmented the effects of D in the microenvironment of this set of NSCLC tumors. The specific impact of D + T on the regulation of angiogenesis and TGFb-mediated immunosuppression warrants further evaluation in a larger set of tumors. Citation Format: Li Cheng, Lydia M. Greenlees, Nicholas M. Durham, Fernanda Pilataxi, Todd Creasy, Brandon W. Higgs, Koustubh Ranade, Katie Streicher. Durvalumab + tremelimumab increase T cells and decrease expression of genes involved in angiogenesis, EMT, and the Th2 pathway in the NSCLC tumor microenvironment [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 1007.