Longitudinal immune characterization of syngeneic tumor models to enable model selection for immune oncology drug discovery

Abstract

BackgroundThe ability to modulate immune-inhibitory pathways using checkpoint blockade antibodies such as αPD-1, αPD-L1, and αCTLA-4 represents a significant breakthrough in cancer therapy in recent years. This has driven interest in identifying small-molecule-immunotherapy combinations to increase the proportion of responses. Murine syngeneic models, which have a functional immune system, represent an essential tool for pre-clinical evaluation of new immunotherapies. However, immune response varies widely between models and the translational relevance of each model is not fully understood, making selection of an appropriate pre-clinical model for drug target validation challenging.MethodsUsing flow cytometry, O-link protein analysis, RT-PCR, and RNAseq we have characterized kinetic changes in immune-cell populations over the course of tumor development in commonly used syngeneic models.ResultsThis longitudinal profiling of syngeneic models enables pharmacodynamic time point selection within each model, dependent on the immune population of interest. Additionally, we have characterized the changes in immune populations in each of these models after treatment with the combination of α-PD-L1 and α-CTLA-4 antibodies, enabling benchmarking to known immune modulating treatments within each model.ConclusionsTaken together, this dataset will provide a framework for characterization and enable the selection of the optimal models for immunotherapy combinations and generate potential biomarkers for clinical evaluation in identifying responders and non-responders to immunotherapy combinations.

Mouse Models of Peritoneal Carcinomatosis to Develop Clinical Applications

“…While syngeneic orthotopic models mimic more efficiently the disease biology of human disease, their main drawback relates to the monitoring of tumor progression, which requires the use of reporter genes, invasive surgical procedures or imaging methods such as real-time in-life fluorescence and bioluminescence imaging. Despite these limitations, syngeneic mouse models offer clues and proofs of concept in immunocompetent hosts and thereby represent an excellent preclinical platform to test compounds based on immuno-oncology targets to treat cancer [ 11 ].…”

Mouse Tumor Models for Advanced Cancer Immunotherapy

“…Undoubtedly, the formation of transplanted tumors is different from tumors originating de novo. Moreover, the tumor microenvironment will be mostly determined by the local innate immune response triggered by injection-induced inflammation and the presence of a large number of tumor cells [23,24]. Usually, tumor cells are injected subcutaneously, as it is easier to track tumor development [25].…”

Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

“…After the lack of cooperation between HCA-EFZP-aPDL1 and the treatments described above in the PC model, we targeted other potential sources of tumor resistance such as macrophages. The MC38 tumor model is characterized by a diverse composition of the leukocyte infiltrate, with a progressive expansion of macrophages and a concomitant reduction in their pro-inflammatory (M1) phenotype [23]. They present reduced IL-12 and iNOS signaling, and activation of the IL-10 pathway [24].…”