BioProject

Murine syngeneic tumor models are the cornerstone of novel immuno-oncology (IO)-based therapy development but the molecular and immunological features of these models are still not clearly defined. More...

Murine syngeneic tumor models are the cornerstone of novel immuno-oncology (IO)-based therapy development but the molecular and immunological features of these models are still not clearly defined. The translational relevance of differences between the models is not fully understood, impeding appropriate preclinical model selection for target validation, and ultimately hindering drug development. Within a panel of commonly-used murine syngeneic tumor models, we showed variable responsiveness to IO-therapies. We employed aCGH, whole-exome sequencing, exon microarray analysis and flow cytometry to extensively characterise these models and revealed striking differences that may underlie these contrasting response profiles. We identified strong differential gene expression in immune-related pathways and changes in immune cell-specific genes that suggested differences in tumor immune infiltrates between models. We further investigated this using flow cytometry, which showed differences in both the composition and magnitude of the tumor immune infiltrates, identifying models that harbor ‘inflamed’ and ‘non-inflamed’ tumor immune infiltrate phenotypes. Moreover, we found that immunosuppressive cell types predominated in syngeneic mouse tumor models that did not respond to immune-checkpoint blockade, whereas cytotoxic effector immune cells were enriched in responsive models. A cytotoxic cell-rich tumor immune infiltrate has been correlated with increased efficacy of IO-therapy in the clinic and these differences could underlie the varying response profiles to IO-therapy between the syngeneic models. This characterisation highlighted the importance of extensive profiling and will enable investigators to select appropriate models to interrogate the activity of IO-therapies as well as combinations with targeted therapies in vivo. Overall design: Mouse syngeneic tumour cell lines were grown in vitro n=1 and in vivo n ≈5 subcutaneously on the backs of mice from their parental strain or orthotopically (see sample records for specific details for each mouse model). Mice were sacrificed when tumours reached an average of 200 mm3. In vitro samples underwent aCGH analysis and transcriptomics analysis while in vivo tumor samples along with a draining lymph node and spleen sample were taken from the same mouse and underwent transcriptomics analysis. Whole exome sequencing and immunophenotyping were also performed on these syngeneic models to in all give a multiomic characterisation of these models. Less...