Abstract B33: Tumor-stromal response to immune checkpoint blockade within patient tissue derived three-dimensional lung tumor models


 The tumor microenvironment is a key regulator of tumor biology and response to therapeutic intervention, with intercellular communication between tumor and stromal cells regulating growth and progression. While two dimensional cultures are commonly utilized for in vitro preclinical studies, they do not recapitulate the tissue microenvironment or three dimensional tissue architecture. Herein, we utilize tissue engineering strategies and patient-derived specimen to develop ex vivo non-small cell lung tumor models. These models allow for evaluation of tumor-stromal interactions and response to immune directed therapies while keeping the native tissue microenvironment intact. For this study, tumor models were generated utilizing remnant lung tumor specimen from consented patients undergoing surgical tumor resection. 5 mm diameter tissue cores were placed in a volume of extracellular matrix within a perfusion bioreactor platform, and through-channels were generated to provide nutrient circulation during ex vivo culture. Spatial profiling using the Nanostring GeoMx platform, multiplex cytokine analysis, histologic and flow cytometric analyses were performed following culture. Primary human tumor specimens cultured ex vivo maintain histologic architecture and representative cell populations following 14 days culture. Tissues treated with an anti-programmed cell death protein 1 (PD-1) blocking antibody showed reduced IL-6 (380.8 ±133.9 pg/mL) levels within the circulating media when compared to IgG control treated tissues (1119 ±382.9 pg/mL, p=0.08). Spatial profiling showed increased proportions of dividing T cells (2.27 ± 1.02 IgG vs. 8.28 ± 1.171 anti-PD-1; p=0.02) and CD8+ memory T cells (0.09 ± 0.09 IgG vs. 1.74 ± 0.64 anti-PD-1; p=0.04) and a trend towards more natural killer cells (3.88 ± 0.73 IgG vs. 6.56 ± 3.14 anti-PD-1; p=0.067), along with decreased proportions of macrophages (14.33 ± 2.16 IgG vs. 6.44 ± 0.59 anti-PD-1; p=0.004) near the tumor in tissues treated with anti-PD-1 when compared to control. Additionally, genes within the tumor immune signature associated with programmed cell death ligand 1 suppression, anti-tumor cytotoxicity and T cell response, including CXCR6, CCL3, NKG7, CMKLR1, CD27 & PSMB10, were upregulated and genes associated with immune suppression, including IDO and HLA-E, were downregulated with anti-PD-1 treatment when compared to IgG control. Moving forward, this platform will allow for extensive characterization of tumor-stromal interactions, response to therapeutic intervention, and therapeutic resistance in a patient specific manner. Funding: Nanostring DSP Cancer Transcriptome Atlas Award; 1R21 CA263365-01A1; Respiratory Health Association Lung Cancer Award (RHA2022-01-LC).
 Citation Format: Kayla F. Goliwas, Anthony M. Wood, Young-il Kim, Joel L. Berry, James M. Donahue, Jessy S. Deshane. Tumor-stromal response to immune checkpoint blockade within patient tissue derived three-dimensional lung tumor models [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B33.