Comparison of the molecular and cellular phenotypes of common mouse syngeneic models with human tumors

Abstract

BackgroundThe clinical success of immune checkpoint inhibitors demonstrates that reactivation of the human immune system delivers durable responses for some patients and represents an exciting approach for cancer treatment. An important class of preclinical in vivo models for immuno-oncology is immunocompetent mice bearing mouse syngeneic tumors. To facilitate translation of preclinical studies into human, we characterized the genomic, transcriptomic, and protein expression of a panel of ten commonly used mouse tumor cell lines grown in vitro culture as well as in vivo tumors.ResultsOur studies identified a number of genetic and cellular phenotypic differences that distinguish commonly used mouse syngeneic models in our study from human cancers. Only a fraction of the somatic single nucleotide variants (SNVs) in these common mouse cell lines directly match SNVs in human actionable cancer genes. Some models derived from epithelial tumors have a more mesenchymal phenotype with relatively low T-lymphocyte infiltration compared to the corresponding human cancers. CT26, a colon tumor model, had the highest immunogenicity and was the model most responsive to CTLA4 inhibitor treatment, by contrast to the relatively low immunogenicity and response rate to checkpoint inhibitor therapies in human colon cancers.ConclusionsThe relative immunogenicity of these ten syngeneic tumors does not resemble typical human tumors derived from the same tissue of origin. By characterizing the mouse syngeneic models and comparing with their human tumor counterparts, this study contributes to a framework that may help investigators select the model most relevant to study a particular immune-oncology mechanism, and may rationalize some of the challenges associated with translating preclinical findings to clinical studies.

Anti-tumor immunity influences cancer cell reliance upon ATG7

“…MC38 are intermediate, as they have substantial immune infiltrate but have limited response to the ICB agents anti-CTLA-4 and anti-PD-L1 and evoke a relatively low T cell-mediated cytolytic activity score. 26,28,34 Given the correlation between immunogenicity and in vivo sensitivity to ATG7 loss, we reasoned that anti-tumor immunity may drive cancer cell reliance upon autophagy.…”

Revolutionizing the landscape of colorectal cancer treatment: The potential role of immune checkpoint inhibitors

“…Both cell lines are derived from carcinogen-induced tumors. 11,13,14 CT-26 is an example of microsatellite stable (MSS) cell line that is established in Balb/c mice and is characterized by harboring KRAS mutation. 15 In contrast, MC38 is established in C57B1/6 mice and represent microsatellite unstable (MSI) colon cancer cell line that is KRAS-wild type but harbors heterozygous mutations in both transformation-related protein (Trp)53 and SMAD4.…”

“…15 In contrast, MC38 is established in C57B1/6 mice and represent microsatellite unstable (MSI) colon cancer cell line that is KRAS-wild type but harbors heterozygous mutations in both transformation-related protein (Trp)53 and SMAD4. 11,13,14 However, both CT-26 and MC38 cells lack APC mutation which is characteristic for the majority of human CRC. 11,13,14 It is noteworthy that CT-26 model is less immunogenic compared to the hypermutated MC38 model.…”

“…11,13,14 However, both CT-26 and MC38 cells lack APC mutation which is characteristic for the majority of human CRC. 11,13,14 It is noteworthy that CT-26 model is less immunogenic compared to the hypermutated MC38 model. 11,13,14 Treatment with immune checkpoint (PD-1/PD-L1) inhibitors augmented the immunoediting in the hypermutated MC38 model.…”

“…11,13,14 It is noteworthy that CT-26 model is less immunogenic compared to the hypermutated MC38 model. 11,13,14 Treatment with immune checkpoint (PD-1/PD-L1) inhibitors augmented the immunoediting in the hypermutated MC38 model. 14 Studies showed that the response of CRC syngeneic models to ICIs is correlated to clinical observations in CRC patients which support the validity of these models as a tool for preclinical investigations on immunotherapeutics.…”