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Abstract
Immune cells play critical functions in cancer, and mice with intact immune systems are vital to understanding tumor immunology. Both genetically engineered mouse models (GEMMs) and syngeneic cell transplant approaches use immunocompetent mice to define immune-dependent events in tumor development and progression. Due to their rapid and reproducible nature, there is expanded interest in developing new syngeneic tools from established primary tumor models. However, few studies have examined the extent that syngeneic tumors reflect the immune profile of their originating primary models. Here, we describe comprehensive immunophenotyping of two well-established GEMMs and four new syngeneic models derived from these parental primary tumors. To our knowledge, this is the first systematic analysis comparing immune landscapes between primary and orthotopic syngeneic tumors. These models all use the same well-defined human-relevant driver mutations, arise at identical orthotopic locations, and are generated in mice of the same background strain. This allows for a direct and focused comparison of tumor immune landscapes in carefully controlled mouse models. We identify key differences between the immune infiltrate of GEMM models and their corresponding syngeneic tumors. Most notable is the divergence of T cell populations, with different proportions of CD8+ T cells and regulatory T cells across several models. We also observe immune variation across syngeneic tumors derived from the same primary model. These findings highlight the importance of immune variance across mouse modeling approaches, which has strong implications for the design of rigorous and reproducible translational studies.
Highlights
Immune cells play critical roles in cancer by impacting tumor growth, therapeutic response, and metastatic progression
We found that levels of M HCIIhi and M HCIIlow TAMs are similar between Undifferentiated Pleomorphic Sarcoma (UPS) primary and syngeneic tumors (Fig. 3E–F). MHCIIhi TAMs are more prevalent than M HCIIlow TAMs in all models, as shown by an M HCIIhi/MHCIIlow ratio > 1 (Supplemental Fig. 4A)
Both genetically engineered mouse models (GEMMs) and syngeneic murine tumor models are vital tools for cancer immunology; there is a need to better understand the critical differences in immune landscapes between these two a pproaches[37]
Summary
Immune cells play critical roles in cancer by impacting tumor growth, therapeutic response, and metastatic progression. Localized injection of tamoxifen (TMX) into the gastrocnemius activates Cre, resulting in KrasG12D activation and p53 loss in muscle satellite cells Both UPS and RMS tumors arise within a native tumor microenvironment, facilitating studies on immune infiltration and treatment r esponse[31]. Because both GEMM approaches use identical initiating mutations in mice of the same background at similar orthotopic locations, these models provide a unique opportunity to directly compare the immune profiles of different preclinical tumor models in genetically matched tumors. To determine if the immune landscapes of syngeneic tumors reflect the profiles of their primary counterparts, we generated four new syngeneic sarcoma models from orthotopically-injected cells named K-Ras Induced Murine Sarcoma (KRIMS) tumors. This study provides the first systematic characterization of intratumoral immune profiles between paired primary and syngeneic tumor models, which has strong implications for the design of preclinical studies using murine approaches
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