The explosion of research in the cancer immunotherapy field has led to a quest for better animal models to validate and develop various immunotherapies. Syngeneic mouse tumor models are one of the best options currently available to select cancers where clinical efficacy may be expected, to test mechanism of action hypotheses, in providing clues for possible biomarkers of immune pharmacodynamic (PD) activity and most successfully for predicting best partners for synergistic combinations. In order to select an appropriate model to evaluate a specific immunotherapy, it is essential to ensure sufficient understanding of the tumor model especially the immunogenicity and the characteristics of the immune infiltrates in the tumor microenvironment. It is also important to understand the dynamics of tumor growth and its effect on the immune landscape in the various peripheral tissues compartments during cancer progression.
We embarked on this study to systematically evaluate the dynamics and kinetics of phenotypic changes in immune cells in tumor, circulation and lymphoid organs with tumor progression in several syngeneic mouse tumor models. Pharmacodynamic evaluations of immune responses in all lymphoid compartments including the TME were made at various time points of tumor progression. Multicolor flow cytometry was performed on TILs, splenocytes and lysed whole blood to evaluate various T cells and the cell surface markers of activation, regulation and exhaustion. Additionally changes in cytokine levels in serum were also analyzed.
Our results show 1) significant changes in the tumor microenvironment (TME) with reference to the various types and functional status of immune cells in the various models and while tumor progression 2) Comparison between the different compartments within each model suggests significant changes in the co-stimulatory and co-inhibitory markers expressed on the TILs and their relative numbers and function in the periphery and other lymphoid compartments. 3) In addition, the dynamic changes observed with tumor progression in this study urge for a continuous assessment of these changes to obtain a complete kinetic picture rather than a snapshot when performing in-vivo biomarker studies in mice.
The information obtained from this study about the TIL and the expression of co-stimulatory/co-inhibitory molecules on these tumor models will enable us to employ a methodical approach when choosing a syngeneic model for efficacy and PD biomarker studies of immuno-modulatory agents under investigation.
All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed.
Citation Format: Sapna Yadavilli, Sabyasachi Bhattacharya, Ashleigh Hahn, Laura Seestaller-Wehr, David Kilian, Meixia Bi, Shu-Yun Zhang, Nicholas Vitali, Michael Adam, Yufeng Li, Niranjan Yanamandra, Roopa Srinivasan, Axel Hoos. Evaluating immune contexture in syngeneic mouse models of cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A149.