VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) and immune checkpoint inhibitors (ICIs) are approved together as a treatment regimen for multiple metastatic cancers, yet the mechanistic basis for this combinatory benefit remains unclear. Previously we have shown that resistance to VEGFR TKI treatment can transiently hijack the secretory machinery typically associated with senescence - the process of cellular aging. Here we report that these senescence-associated secretory programs can also drive immune cell activation, potentially ‘priming' the tumor for PD-1 pathway inhibition. Using a novel live-cell sorting method based on C12FDG - a substrate for senescence-associated beta-galactosidase activity - we isolated senescence-marker (SM) expressing VEGFR TKI-treated cells for transcriptomic analysis. SM+ cell populations were enriched for senescence, immune, and interferon secretory processes, with a unique gene signature validated using published preclinical and clinical datasets. Notably, SM+ cells were found to be more sensitive to CD8 T-cell mediated tumor inhibition in vivo and ex vivo and be sensitive to PD-L1 blockade and inhibitors of mTOR, a key secretory regulator. Together, these results suggest VEGFR TKI controlled secretory programs contributing to resistance can simultaneously prime the tumor microenvironment for immune cell activation, providing an explanation for improved effects of antiangiogenic and immunotherapy combinations in patients.

Citation Format: Melissa Dolan, Yuhao Shi, James W. Hill, Michalis Mastri, Cristina Vaghi, Joseph Barbi, Sebastien Benzekry, John M. Ebos. Hijacked senescence secretomes as 'immune primers' of antiangiogenic TKI efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3195.