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
Authors: Cheng Li , Greenlees Lydia M. , Durham Nicholas M. , Pilataxi Fernanda , Creasy Todd , Higgs Brandon W. , Ranade Koustubh , Streicher Katie 
Published: August 2018

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 (&gt; 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 &gt; 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; &gt; 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.