VSV∆M51 drives CD8+ T cell-mediated tumour regression through infection of both cancer and non-cancer cells
Jahanara Rajwani, Daniil A. Vishnevskiy, Madison Turk, Victor Naumenko, Chris Gafuik, Dae‐Sun Kim, Laura Mah, Shannon Snelling, Gerone A. Gonzales, Jingna Xue, Ayan Chanda, Kyle Potts, Hayley M. Todesco, Keith C.K. Lau, Karys Hildebrand, Jennifer A. Chan, Shan Liao, Michael J. Monument, Martin Hyrcza, Pinaki Bose, Craig N. Jenne, Johnathan Canton, Franz J. Zemp, Douglas J. Mahoney
Abstract
Oncolytic viruses (OV) are designed to selectively infect and kill cancer cells, while simultaneously eliciting antitumour immunity. The mechanism is expected to originate from infected cancer cells. However, recent reports of tumour regression unaccompanied by cancer cell infection suggest a more complex mechanism of action. Here, we engineered vesicular stomatitis virus (VSV)ΔM51-sensitive and VSVΔM51-resistant tumour lines to elucidate the role of OV-infected cancer and non-cancer cells. We found that, while cancer cell infections elicit oncolysis and antitumour immunity as expected, infection of non-cancer cells alone can also contribute to tumour regression. This effect is partly attributed to the systemic production of cytokines that promote dendritic cell (DC) activation, migration and antigen cross-presentation, leading to magnified antitumour CD8+ T cell activation and tumour regression. Such OV-induced antitumour immunity is complementary to PD-1 blockade. Overall, our results reveal mechanistic insights into OV-induced antitumour immunity that can be leveraged to improve OV-based therapeutics. The role of non-cancer cells infected by oncolytic viruses (OV) in cancer regression remains elusive. Here the authors engineer OV-sensitive and OV-resistant cancer cell lines and show that OV infection of non-cancer cells can elicit effective antitumour immunity via enhancing DC function and CD8+ T cell activation.