VISTA, also known as PD1H, is an immune-checkpoint receptor mainly expressed in immune cells, including macrophages, conventional dendritic cells, monocytes and circulating neutrophils. As a negative regulator of T cell activation, VISTA inhibits T cell proliferation and attenuates the production of cytokines. Studies have shown that VISTA expression is increased in infiltrating immune cells found in the tumor microenvironment and that blocking pathways that lead to VISTA activation can enhance antitumor immune responses in mice. Based on this, antibodies targeting VISTA are promising leads for cancer therapy. Preclinical efficacy evaluation of antibodies again human VISTA requires the expression of human VISTA in animal models, since difference in extracellular domains may affect antibody recognition while the overall homology between the two proteins is only 77%.

To meet this need, we established a humanized mouse model in which the extracellular domain of mVISTA is replaced with that of hVISTA while the trans-membrane and cytoplasmic domains remain intact. In order to confirm the activity of the chimeric protein in our mice, we evaluated the anti-tumor effect of proven VISTA antibodies in homozygous hVISTA mice engrafted with CT26 tumor subcutaneously. Consistent with previous studies, the growth of CT26 tumor was inhibited after VISTA antibody treatment, indicating the humanized VISTA mice are suitable for efficacy evaluation of human VISTA antibodies.

Moreover, we evaluated the anti-tumor effect of a combination of PD-L1 antibody and VISTA antibody in these mice. Interestingly, the combined use of PD-L1 antibody and VISTA antibody led to significantly enhanced tumor regression than either antibody. Taken together, BALB/c-hVISTA mouse is a novel non-human animal model appropriate for preclinical efficacy study of human VISTA antibodies.

Citation Format: Weiwei Yu, Honghong Bao, Shuai Li, Chao Ju, Hongyan Sun, Hao Qi, Cunxiang Ju, Jing Zhao, Xiang Gao. BALB/c mice with humanized VISTA: A novel GEMM for preclinical evaluation of therapeutic antibodies against VISTA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5194.