Combined immunotherapy potentiates CD8+ cytotoxic T-cell infiltration in a spontaneous mouse model of immune-excluded gastric cancer

In this study, we characterized the transgenic mouse model of stomach adenocarcinoma CEA424-SV40 T Ag. Transgenic mice, generated in Prof Wolfgang Zimmermann’s lab (Ludwig-Maximilian University, Munich) (Tompson et al. Int J Cancer, 2000), produce spontaneous tumors in the pyloric region of the stomach in a time-dependent stage wise process. Combining multiple techniques, including transcriptomic analysis, we investigated the composition of the tumor microenvironment over time. We found that gastric tumors in CEA424-SV40 Tag present features of an immunosuppressive environment and are refractory to different immunotherapies. Comparing the expression profiles of tumors at early (day 60) and late stage (day80) we observed overexpression of stroma remodelling signatures, predicting poor overall survival in human patients of stomach adenocarcinoma. Finally, we demonstrated that combination of stroma-targeted T cell activation and PD-L1 inhibition potentiated CD8+ T cell migration to tumors. Our data demonstrate that the CEA424-SV40 T Ag model is clinically relevant and constitute an ideal platform to develop new immunotherapies, such as tumor-targeted stimulation of T cells combined with immune checkpoint blockade. Total RNA was exctracted from bulk pyloric tissue collected from 60 or 80 days-old wild-type C57BL/6 mice or CEA424-SV40 T Ag transgenic mice, and profiled by RNA-seq