SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade
Adam Grippin, Christiano Marconi, Sage Copling, Nan Li, Chen Braun, Cole Woody, Elliana Young, Priti Gupta, Min Wang, Annette Wu, Seong Dong Jeong, Dhruvkumar Soni, Frances Weidert, Chao Xie, Eden Goldenberg, Andrew Kim, Chong Zhao, Anna DeVries, Paul Castillo, Rishabh Lohray, Michael K. Rooney, Benjamin R. Schrank, Yifan Wang, Yifan Ma, Enoch Chang, Ramez Kouzy, Kyle Dyson, Jordan Jafarnia, Nina Nariman, Gregory W. Gladish, Jacob New, Ada Argueta, Diana Amaya, Nagheme Thomas, Andria Doty, Joe Chen, Nikhil Copling, Gabriel Alatrash, Julie M. Simon, Alicia Bea Davies, William Dennis, Richard Liang, Jeff Lewis, Xiong Wei, Waree Rinsurongkawong, Ara A. Vaporciyan, Andrew Johns, D3CODE Team, Ashley Aaroe, Sanu Abraham, Lee Andrews, Kiran K. Badami, Janna A. Baganz, Pratibha Bajwa, Gregory Barbosa, Hannah C. Beird, K Brock, Elizabeth M. Burton, Juan P. Cata, Caroline Chung, Catherine M. Claussen, John Crommett, Michael Cutherell, Bouthaina S. Dabaja, Hiba Dagher, Kevin M. Daniels, Mary Domask, Giulio Draetta, Paul Edelkamp, Sarah C. Fisher, Katy Elizabeth French, P. Andrew Futreal, Maria Gaeta, Myrna C. B. Godoy, Drew Goldstein, Jillian R. Gunther, Kate Hutcheson, David A. Jaffray, Jeff Wang Jin, Teny Matthew John, Trey Kell, Mark Knafl, Rayson C. Kwan, J. Jack Lee, Jennifer K. Litton, Kevin W. McEnery, Mary Anne McGuire, Benjamin Mescher, Tejo Musunuru, Mayoora Muthu, Joseph Nates, Craig S. Owen, Priyadharshini Padmakumar, Nicholas Palaskas, Jay J. Patel, Sabitha Prabhakaran, L. Ramsey, Vinod Ravi, Cristhiam Rojas Hernandez, Bilja Sajith
Abstract
Immune checkpoint inhibitors (ICIs) extend survival in many patients with cancer but are ineffective in patients without pre-existing immunity1–9. Although personalized mRNA cancer vaccines sensitize tumours to ICIs by directing immune attacks against preselected antigens, personalized vaccines are limited by complex and time-intensive manufacturing processes10–14. Here we show that mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to ICIs. In preclinical models, SARS-CoV-2 mRNA vaccines led to a substantial increase in type I interferon, enabling innate immune cells to prime CD8+ T cells that target tumour-associated antigens. Concomitant ICI treatment is required for maximal efficacy in immunologically cold tumours, which respond by increasing PD-L1 expression. Similar correlates of vaccination response are found in humans, including increases in type I interferon, myeloid–lymphoid activation in healthy volunteers and PD-L1 expression on tumours. Moreover, receipt of SARS-CoV-2 mRNA vaccines within 100 days of initiating ICI is associated with significantly improved median and three-year overall survival in multiple large retrospective cohorts. This benefit is similar among patients with immunologically cold tumours. Together, these results demonstrate that clinically available mRNA vaccines targeting non-tumour-related antigens are potent immune modulators capable of sensitizing tumours to ICIs. mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.