Abstract LB-C16: The percentage of tumor infiltrating lymphocytes in a panel of solid cancer PDX models correlates with a specific human cytokine pattern in peripheral blood of the tumor bearing animal
Authors: Oswald Eva , Edinger Anna , Peille Anne-Lise , Klett Hagen , Schueler Julia 
Published: March 2020

In the advent of immune modulatory compounds being part of most of the oncology drug development pipelines, the available preclinical models have to be characterized with respect to their interaction with the tumor microenvironment in general and with the immune cells of the host specifically. In the current study we analyzed 31 PDX models covering a broad range of solid cancer entities with regard to the phenotypic characteristics in a humanized environment. Well established PDX models from six different entities (breast, colon, renal, pancreatic, NSCL cancer and glioblastoma) were implanted subcutaneously into immune-compromised mice substituted with CD34+ hematopoietic stem cells (hu-mice). Tumor characterization included: tumor growth curves, take rates, human immune cell infiltrates of tumor (=TILs), peripheral blood and bone marrow (determined by flow cytometry, FC, and IHC) and secretion of human as well as murine cytokines in mouse serum (bead array: human 40plex (Biorad, #171AK99MR2; murine 23plex (Biorad, #M60009RDPD). The panel of 31 different PDX models of solid cancer displayed a distinct TIL and cytokine profile per model. The analysis of TILs revealed a large bandwidth of immune cell infiltration in the respective model ranging from 94% huCD45+ cells (renal cancer RXF 2773) to 3.54% huCD45+ (NSCLC LXFA 1041). Of note, the percentage and phenotype of the TILs was not related to the percentage and phenotype of the human immune cells in the BM or peripheral blood. In a next step, we categorized the PDX models into hot (&gt;5% TILs =huCD45+) and cold (&lt;5% TILs=huCD45+) tumors and compared the two groups with regard to the different read-outs. Differences between the two groups were found with regard to their sensitivity towards checkpoint inhibitor treatment (&gt;5% TILS were more sensitive), the human cytokine profile and their CD4/CD8. A trend towards a higher mutational burden was observe in the group with &gt;5%TILs. No difference between the two categories was determined in TIL composition (despite CD4/CD8 ratio), tumor growth behavior and secretion of mouse cytokines. Taken together, the characterization of PDX models with respect to their TIL composition facilitates model selection for innovative drugs in the immune-oncology field. The possibility to discriminate hot vs cold tumors by a minimal-invasive method like serum analysis of cytokine expression profile as potential biomarker will help to characterize the complete PDX collection of more than 500 models but will as well serve as additional read-out in preclinical I-O studies.

Citation Format: Eva Oswald, Anna Edinger, Anne-Lise Peille, Hagen Klett, Julia Schueler. The percentage of tumor infiltrating lymphocytes in a panel of solid cancer PDX models correlates with a specific human cytokine pattern in peripheral blood of the tumor bearing animal [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-C16. doi:10.1158/1535-7163.TARG-19-LB-C16