Abstract A030: CD4 neoantigen mRNA vaccine enhances endogenous CD8 responses and tumor control
Authors: Balanca Camille-Charlotte , Capietto Aude-Hélène , Carbone Catherine , Gutierrez Alan , Chestnut Yajun , Duong Ellen , Anand Aditya , Antonelli Anthony , Cheung Jeanne , Luoh Shiuh , Nissembaum Ariane , Hokeness Keiko , Wichner Sara , Freund Emily , Javinal Vincent , Bouziat Romain , Gober Joshua , ElSohly Adel , Linehan Jon , Sahin Ugur , Delamarre Lélia , Mellman Ira 
Published: October 2024

CD4 T cells have long been known to be critical for priming CD8 T cells, a process referred to as CD4 T cell help. Recent data have suggested that CD4 help may be delivered at the surface of conventional type 1 dendritic cells (cDC1s), which can efficiently present antigens (Ag) on both MHC class I and class II molecules. However, the actual mechanisms underlying CD4 T cell help remain poorly characterized. We sought to understand how anti-tumor T cell responses are generated in the context of mRNA vaccines, which have been shown to elicit protective CD4 and/or CD8 T cells. For this purpose, we compared two mRNA-Lipoplex (mRNA-LPX) vaccines that express a single MHC-II-restricted Ag either tumor-specific (neoAg) or tumor-irrelevant. mRNA-LPX is injected intravenously and taken up predominantly by cDCs in the spleen.As expected, both vaccines elicited systemic CD4 T cell responses. However, only the anti-tumor CD4 T cell response elicited the accumulation of tumor-infiltrating CD8 lymphocytes (CD8 TILs) that led to tumor regression in a CD8-dependant manner. Single cell RNA-sequencing revealed higher expression of effector molecules and genes associated with stem-like progenitor T cell states in CD8 TILs following neoAg vaccine. In contrast, inhibitory molecules were down-regulated in CD8 TILs from neoAg-vaccinated mice.We next characterized the role of cDCs in the response to the vaccines. We found that both mRNA-LPX vaccines induced better maturation of cDC1s than cDC2s in the spleen. Surprisingly, priming of CD4 T cells was dependent on cDC1s, rather than cDC2s. cDC1s were also required for neoAg CD4 vaccine-induced CD8 TIL accumulation and for vaccine efficacy. We investigated whether neoAg-specific CD4 T cells were i) sufficient to enhance anti-tumor CD8 responses and ii) needed to maintain effector CD8 TIL activity in situ. Using adoptive cell transfer (ACT) into the tumor, we found that the transfer of neoAg-specific CD4 T cells alone significantly delayed tumor growth, suggesting an increased CD8 TIL activity. Interestingly, while the transfer of CD8 TILs alone was insufficient to control tumors; ACT of both CD4 and CD8 T cells was required for efficient tumor rejection. cDC1s were required for the efficacy of both, the ACT of CD4 T cells alone and the CD4 and CD8 ACT combination. Taken together, our data suggest a novel mechanism whereby immunizing with exogenous CD4 T cell epitopes can produce tumor immunity by generating endogenous CD8 responses. These results emphasize the importance of cDC1s for both, eliciting tumor-specific CD4 T cells in the setting of mRNA-LPX vaccine expressing a single MHC-II-restricted Ag and improving in situ anti-tumor CD8 responses and tumor control. We are currently investigating the mechanisms and location of the MHC-II-restricted neoAg dependent-cDC1 help using both in vivo and cell culture approaches.This model provides fundamental insight for the development of cancer vaccines and highlights the need of tumor-specific CD4 T cells and mature tumor-Ag loaded cDC1s.

Citation Format: Camille-Charlotte Balanca, Aude-Hélène Capietto, Catherine Carbone, Alan Gutierrez, Yajun Chestnut, Ellen Duong, Aditya Anand, Anthony Antonelli, Jeanne Cheung, Shiuh Luoh, Ariane Nissembaum, Keiko Hokeness, Sara Wichner, Emily Freund, Vincent Javinal, Romain Bouziat, Joshua Gober, Adel ElSohly, Jon Linehan, Ugur Sahin, Lélia Delamarre, Ira Mellman. CD4 neoantigen mRNA vaccine enhances endogenous CD8 responses and tumor control [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A030.