Immunotherapy efficacy assessment and metastases studies: tHIS model is highly permissive to engraftment
Another important advantage of these mice is their ability to exhibit the dynamic interactions between tumor, tumor microenvironment (TME), and human immune system: this is critical to study, predict and overcome potential immunotherapeutic resistance and side effects in clinical applications. In 2021, Marín-Jiménez and colleagues investigated immune infiltration in reconstituted BRGS-HIS mice engrafted with a great variety of tumors (e.g., breast, adrenocortical, lung, colorectal, pancreatic, melanoma and hematological malignancies) and treated with checkpoint blockade and/or other immunotherapies. Importantly, they demonstrated that the TME of engrafted HIS mice varies by tumor type and combination treatments, mirroring what is observed in humans.3 Moreover, they found that BRGS-HIS mice recapitulate TME in regard to immune infiltration, similar to what was previously observed using the same model.4 Taken together, these findings suggest that the BRGS-HIS model represents a reliable tool to study TME complexity and heterogeneity, and its evolution during drug treatment.
Last but not least, BRGS-HIS mice were successfully used to study metastasis development. In 2018, Gammelgaard and colleagues demonstrated that BRGS-HIS mice consistently develop primary tumors that grow close to synchronous (unlike those reported in NSG-HIS animals), form spontaneous metastases (Fig.2A-B), and display immune escape mechanisms (Fig.2C), such as recruitment of Tregs and PDL1 expression by immune and cancer cells, similar to patients.4
Overall, these results demonstrate that BRGS-HIS mice allow to rapidly test multiple, immune-related therapeutics for tumors originating from unique clinical samples. In addition, this model is ideally suited to assess changes in tumor immunogenicity using different cancer cells and treatments, and to analyze their effects on a human immune response with data from multiple mice, prior to clinical trials. Interestingly, another study also showed that the same preclinical model can be used as a predictive tool for immunotherapy treatment when engrafted with a patient matched tumor, i.e. as an avatar of the patient.5
Taken together, these different publications show that the BRGS-HIS model, and its upgrade BRGSF-HIS, are highly permissive to engraftment and thus represent an optimal model to study and predict human immune responses to immunotherapies in vivo.
The BRGSF-HIS mouse, is available at genOway, designer and provider of multiple preclinical models in several research areas, including immuno-oncology, metabolism, cardiovascular diseases, and neuroscience.
- Tentler, J. J. et al. RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer. BMC Cancer 20, 1063 (2020).
- Capasso, A. et al. Characterization of immune responses to anti-PD-1 mono and combination immunotherapy in hematopoietic humanized mice implanted with tumor xenografts. J. immunotherapy cancer 7, 37 (2019).
- Marín-Jiménez, J. A. et al. Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes. Front. Immunol. 12, 607282 (2021).
- Gammelgaard, O. L., Terp, M. G., Preiss, B. & Ditzel, H. J. Human cancer evolution in the context of a human immune system in mice. Mol Oncol 12, 1797–1810 (2018).
- Lang J, Capasso A, Jordan KR, French JD, Kar A, Bagby SM, Barbee J, Yacob BW, Head LS, Tompkins KD, Freed BM, Somerset H, Clark TJ, Pitts TM, Messersmith WA, Eckhardt SG, Wierman ME, Leong S, Kiseljak-Vassiliades K. Development of an Adrenocortical Cancer Humanized Mouse Model to Characterize Anti-PD1 Effects on Tumor Microenvironment. J Clin Endocrinol Metab. 2020 Jan 1;105(1):26–42.