Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery

Abstract

(word count: 239):Murine syngeneic tumor models are critical to novel immuno-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. Across a panel of commonly-used murine syngeneic tumor models, we showed variable responsiveness to immunotherapies. We employed array comparative genomic hybridization, whole-exome sequencing, exon microarray analysis, and flow cytometry to extensively characterize these models, which 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. Further investigation using flow cytometry 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. We also 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 immunotherapies in the clinic and these differences could underlie the varying response profiles to immunotherapy between the syngeneic models. This characterization highlighted the importance of extensive profiling and will enable investigators to select appropriate models to interrogate the activity of immunotherapies as well as combinations with targeted therapies in vivo.4

Functionally significant metabolic differences between B and T lymphocyte lineages

“…Our data show that even non-activated Tcells are more motile than B-cells. 75 Our study thus underlines a number of previously under-appreciated metabolic distinctions between B-and T-cells that are likely to be of substantial functional relevance in disease microenvironments. Aerobic glycolysis, and not mitochondrial ATP, has been found to be essential for motility in other cell types as well, and has been associated with fluctuations in membrane pump.…”

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

“…MC-38 is derived from a colorectal (CRC) tumour and has a predominant infiltration of myeloid cells in relation to T and NK cells. 17 MC-38 tumours were modestly sensitive to either checkpoint blockade (αPD-1, αCTLA-4 and αPD-L1) or mTORC1/2 inhibiton as a monotherapy. However significant anti-tumour effects were observed when combining vistusertib and checkpoint blockade (Fig.…”

Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma

“…1 Moreover, another recent study showed that murine cancer cell lines with higher mutational burden (e.g., cell lines derived from carcinogen-induced tumor) respond better to immune-checkpoint therapy than those with lower mutational burdens (e.g., cell lines derived from spontaneous or GEMM-derived tumors). 37 Thus, it is tempting to speculate that GL261-based gliomas are more representative of medium-to-hyper mutant GBM rather than typical low mutational burden (adult) GBM, and hence are more responsive to Figure 6. Anti-PD1 mono-immunotherapy exhibits the highest therapeutic efficacy against preclinical glioma.…”