Preclinical platform using a triple-negative breast cancer syngeneic murine model to evaluate immune checkpoint inhibitors

crossref(2022)

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摘要
Abstract Purpose To evaluate the feasibility of syngeneic mouse models of breast cancer by analyzing the efficacy of immune checkpoint inhibitors (ICIs) and potential predictive biomarkers. Methods Four syngeneic mouse models of triple-negative breast cancer (TNBC) JC, 4T1, EMT6 and E0771 cells were injected subcutaneously. When the tumor reached 50–100 mm3, each mouse model was divided into treatment (murine PD-1 antibody) and no-treatment control. Treatment group is further divided into the responder and nonresponder groups. Potential predictive biomarkers were evaluated by analyzing serum cytokines, peripheral blood T cells and tumor infiltrating immune cells. Results The JC model showed the highest tumor response rate (40%, 4/10) of syngeneic models: 4T1 (36%, 4/11), EMT6 (36%, 4/11), or E0771 model (23%, 3/13). Early change of tumor size at 7 days post PD-1 inhibitor treatment predicted the final efficacy of PD-1 inhibitor. Peripheral blood CD8 + and CD4 + T cells with or without Ki67 expression at 7 days post-PD-1 inhibitor treatment were higher in the finally designated responder group than in the nonresponder group. At the time of sacrifice, analyses of tumor infiltrating lymphocytes consistently supported these results. Furthermore, serum IFN-γ at 7 days post-PD-1 inhibitor treatment was also higher in responders than in nonresponders, suggesting that early changes of these markers could be predictive biomarkers of the final efficacy of ICIs. Conclusions Our syngeneic mouse model of TNBC is a feasible preclinical platform to evaluate ICI efficacies combined with other drugs and predictive biomarkers in the screening period of immune-oncology drug development.
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