Abstract:
Among the emerging strategies in cancer immunotherapy, individualized mRNA-based vaccines have garnered significant attention for their ability to stimulate a robust tumor-specific immune response by targeting patient-specific immunogenic tumor mutations. Although the focus of cancer vaccines has mainly been on targeting CD8+ T cells, there is substantial evidence to support the importance of eliciting CD4+ T cell responses.
To explore this, we developed an mRNA lipoplex vaccine encoding a single MHCII-restricted neoantigen. The vaccine elicited T follicular helper (Tfh) and T helper 1 (Th1) CD4 T cell responses while decreasing regulatory T cells, and induced rejection of established tumors in mice, independently of MHCII expression by cancer cells. IL-21 and IFN-????, which are essential for Tfh and Th1 functionality respectively, were crucial for anti-tumor activity.
Furthermore, our study revealed that neoantigen-specific vaccination promoted B cell maturation in tumor and the generation of neoantigen-specific antibodies exhibiting anti-tumor activity, likely through antibody-dependent cellular cytotoxicity (ADCC).
Furthermore, we found that EnRV RNA-LPX vaccination stimulated the expansion and function of intratumoral CD8 T cells and depleting CD8 T cells led to a complete loss of anti-tumor activity. Conventional type 1 dendritic cells (cDC1s) were found to play a crucial role in eliciting neoantigen-specific CD4 T cells, and in facilitating CD4 T cell help to CD8 T cells within the tumor microenvironment, ultimately driving tumor regression. These results underscore the importance of cDC1s in orchestrating the overall immune response following MHCII RNA-LPX vaccination. As the vaccine did not contain MHCI epitopes, our data demonstrate that only eliciting a CD4+ response can be sufficient to enhance endogenous CD8+ responses to tumor antigens presented by cDC1s.
Altogether, an RNA-LPX vaccine encoding for a single MHCII-restricted neoantigen successfully initiates a strong and coordinated immune response, leading to tumor elimination. These findings support exploring novel strategies, including cancer vaccines, aimed at augmenting CD4 T cell responses, which hold a significant potential for enhancing antitumor efficacy.
