A kinetic analysis of tumor gene expression and cellular changes following immune checkpoint inhibition in the MC38 colon carcinoma model

The clinical success of immune checkpoint therapies such as PD-1, PD-L1, and CTLA-4 inhibitory antibodies has stimulated interest in a wide range of approaches to cancer immunotherapy. Development of these new modalities requires robust, well characterized preclinical animal models to evaluate efficacy and potential toxicities. Preclinical efficacy assessments of novel immune-oncology therapies requires a functional immune system which limits the usefulness of traditional xenograft models and drive the use of humanized (human immune cell engrafted animals) and syngeneic model systems. Syngeneic mouse tumors are popular model systems in which to evaluate these novel therapies due the presence of fully intact mouse immune system and ease of accessibility. The MC38 mouse colon cancer model is popular for efficacy assessment studies due to its responsiveness to typical immune checkpoint inhibitors (ICI). We endeavored to characterize the kinetic immune response to checkpoint inhibitors (anti-PD-1 + anti-CTLA-4) in MC38 tumors using flow cytometry and gene expression analysis. Gene expression analysis provided a signature of gene changes that correlate to immune driven changes in tumor growth and may be used in preclinical pharmacodynamics studies as evidence of mode of action for other novel immune-oncology therapies. In addition, gene over-representation analysis highlighted the presence and involvement of B cell populations in the MC38 tumor environment which was supported by IHC data that show distinctive B cell staining in what resemble tumor associated tertiary lymphoid structures. These findings provide a greater understanding of the ICI response in the MC38 tumor model and may inform mode of action study designs for other novel immuno-oncology therapies. Citation Format: Patrick Fadden, Thi Bui, Kelli Davis, David Hurtado, Ian Belle, Katherine Krontz, Jacob Hauser, Cristina Sokolowski, Na Li, Kyle Takayama, Paula Miliani de Marval, David Harris, Edgar Wood. A kinetic analysis of tumor gene expression and cellular changes following immune checkpoint inhibition in the MC38 colon carcinoma model [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 A015. doi:10.1158/1535-7163.TARG-19-A015