879 Deep immunoprofiling of tumor mouse models for preclinical studies

Le résumé fourni par la source

Background Preclinical tumor oncology research relies on analysis of tumor cell lines implanted into immune-competent mice in case of syngeneic mouse tumors, or severely immune-deficient mouse models carrying nude, SCID IL-2Rg or Rag mutations in case of human Cell derived xenograft (CDX) tumors. Currently, the most advanced strains are the nonobese diabetic, severe combined immunodeficiency (NOD-SCID) mouse with complete disruptions in the interleukin-2 (IL-2) common g-chain (IL2Rg-/-) receptor (NSG) and BALB/cRag2-/-IL2Ra-/-SirpaNOD mice (BRGS). A further refinement of later approach consists in implanting CDX onto ‘humanized’ mice, in which a human immune system has been reconstituted following human CD34 hematopoietic stem and progenitor cell (HSPCs) engraftment. To decipher the impact of treatments, cellular phenotyping of tumor infiltrating leukocytes and in peripheral organs is necessary. This primary screen aims to quantify the different cell populations in a syngeneic tumor model. Methods In order to increase our understanding in the precise mode of action of anti-PD1 treatment at the cellular level in sensitive and unsensitive models, we investigated immunophenotypes and responses to immune checkpoint inhibitor (ICI) of several hallmark tumor models (MC38/CT26/B16F10/B16-OVA/RENCA/EMT6) in immunocompetent mouse models by flow and mass cytometry as well as one CDX (PANCO8.13) in humanized NXG mouse. Results We compared growth kinetics and profiled the immune cell composition of tumor microenvironment (TME), draining lymph node (dLN) and blood in order to establish immune-phenotypic cell signatures that correlates with treatment efficacy. Supervised, unsupervised and integrative data analysis are used to identify significant changes across different experimental settings. Our results indicate that each model possesses a unique tumor-immune infiltrate profile that could be modulated with selective immunotherapies. Conclusions Overall, this study provides an important resource of highly-characterized tumor models that will drive selection of the most appropriate model to test novel immunotherapeutic agents and enhance our translation of knowledge from syngeneic models to human tumors.

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