A single MHCII neoepitope mRNA vaccine elicits CD4 T- and B- cell responses promoting endogenous CD8 anti-tumor immunity
Year: 2025
Type: preprint
Abstract: Summary Recent progress in therapeutic cancer vaccines has shown promising clinical activity, especially when targeting MHC class I (MHCI) neoantigen-specific CD8 + T cell responses in post-surgical patients. To explore the role of CD4 + T cells in vaccine-dependent tumor rejection, we constructed an mRNA lipoplex vaccine encoding a single MHCII-restricted neoantigen. The vaccine elicited Tfh and Th1 cell responses while decreasing Tregs, leading to rejection of established tumors in mice. IL-21 and IFN-γ, crucial for Tfh and Th1 function respectively, contributed to anti-tumor activity. B cells and neoantigen-specific antibodies were also shown to participate in vaccine efficacy. Additionally, conventional type 1 dendritic cells (cDC1s) were essential for eliciting vaccine-induced CD4 + T cells, and both cDC1s and CD4 + T cells were required to enhance endogenous CD8 + responses, which were crucial for tumor control. Our results suggest that immunizing against MHCII neoantigens alone is sufficient to orchestrate a potent and cooperative immune response against cancer.
Authors: Aude-Hélène Capietto, Camille-Charlotte Balança, Romain Bouziat, Thomas D. Wu, Joshua Gober, Catherine Carbone, Ariane Nissenbaum, Reyhane Hoshyar, Marshleen Yadav, Alan Gutierrez, Yajun Chestnut, Vincent Javinal, Hari Menon, Spyros Darmanis, Marco de Simone, Yonglian Sun, Dhaya Seshasayee, Maciej Paluch, Beyza Bulutoglu, Tamaki Jones, Yingyun Wang, Lisa Liao, Ellen Duong, Aditya Anand, Anthony Antonelli, Yoko Oei, Jeanne Cheung, Shiuh-Ming Luoh, James Ziai, Jessica Preston, Jeffrey Hung, Emily Freund, Sara Wichner, Jaehak Oh, Siri Tahtinen, Ugur Sahin, Adel ElSohly, Jill Schartner, Lélia Delamarre, Ira Mellman, Jonathan L. Linehan
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funder: Genentech
OpenAlex ID: W4411293593