A single MHCII neoepitope mRNA vaccine elicits CD4 T- and B- cell responses promoting endogenous CD8 anti-tumor immunity

Capietto, A.-H.; Balanca, C.-C.; Bouziat, R.; Wu, T.; Gober, J.; Carbone, C.; Nissenbaum, A.; Hoshyar, R.; Yadav, M.; Gutierrez, A.; Chestnut, Y.; Javinal, V.; Menon, H.; Darmanis, S.; de Simone, M.; Sun, Y.; Seshasayee, D.; Paluch, M.; Bulutoglu, B.; Jones, T.; Wang, Y.; Liao, L.; Duong, E.; Anand, A.; Antonelli, A.; Oei, Y.; Cheung, J.; Luoh, S.-M.; Ziai, J.; Preston, J.; Hung, J.; Freund, E.; Wichner, S.; Oh, J.; Tahtinen, S.; Sahin, U.; ElSohly, A.; Schartner, J.; Delamarre, L.; Mellman, I.; Linehan, J.

doi:10.1101/2025.06.09.657934

Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.06.09.657934

A single MHCII neoepitope mRNA vaccine elicits CD4 T- and B- cell responses promoting endogenous CD8 anti-tumor immunity

View original source ↗Export metadata ↓

Abstract

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-{gamma}, 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.

Explore related subjects

immunology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Capietto, A.-H., Balanca, C.-C., Bouziat, R., Wu, T., Gober, J., Carbone, C., Nissenbaum, A., Hoshyar, R., Yadav, M., Gutierrez, A., Chestnut, Y., Javinal, V., Menon, H., Darmanis, S., de Simone, M., Sun, Y., Seshasayee, D., Paluch, M., Bulutoglu, B., Jones, T., Wang, Y., Liao, L., Duong, E., Anand, A., Antonelli, A., Oei, Y., Cheung, J., Luoh, S.-M., Ziai, J., Preston, J., Hung, J., Freund, E., Wichner, S., Oh, J., Tahtinen, S., Sahin, U., ElSohly, A., Schartner, J., Delamarre, L., Mellman, I., Linehan, J.. 2025-06-12. A single MHCII neoepitope mRNA vaccine elicits CD4 T- and B- cell responses promoting endogenous CD8 anti-tumor immunity. https://doi.org/10.1101/2025.06.09.657934

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Ksp37 is a rapidly mobilized NK cell secretory protein that engages FGF2

A key feature of natural killer (NK) cells is their preloaded arsenal of effector molecules, allowing them to rapidly respond upon activation. In this study, we characterized a previously unexplored secretory protein, termed killer-specific secretory protein of 37 kDa (Ksp37), which is highly abundant in differentiated CD56dim NK cells. Ksp37 is rapidly secreted in a dose-dependent and JAK-1 dependent manner upon low levels of cytokine stimulation, making it a sensitive readout for NK cell activation. Following secretion, intracellular levels were rapidly replenished, preserving responsiveness to subsequent cytokine stimulation. We found that Ksp37 is stored in polarized intracellular compartments distinct from those containing canonical cytotoxic effector molecules, including granzyme B and perforin, which require stronger stimulation for release. Lastly, we identified Ksp37 as a novel binding partner of fibroblast growth factor 2 (FGF2). This opens new avenues of exploration for the role of NK cells in remodeling their extracellular environment by modulating the FGF2-FGFR1 axis, which plays a key role in tumor growth, angiogenesis and tissue repair.

immunology↗

bioRxiv2026

ACE-engineered human iPSC-derived neutrophils enhance host defense against multidrug-resistant bacterial infections

Severe neutropenia predisposes patients to life-threatening infections, while donor-dependent granulocyte transfusions are limited by availability and variable cell quality. Here, we engineered human induced pluripotent stem cells (iPSCs) to constitutively or inducibly express angiotensin-converting enzyme (ACE) and differentiated them into functional ACE-engineered neutrophils (ACE-iNeu). ACE expression enhanced granulocytic maturation, reactive oxygen species generation, inflammatory cytokine production, and antimicrobial signaling. ACE-iNeu exhibited enhanced bactericidal activity against methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa. Following adoptive transfer into neutropenic mice, ACE-iNeu significantly reduced circulating and tissue bacterial burdens. Integrated metabolomic and transcriptomic analyses revealed ACE-associated alterations in adenine nucleotide abundance and developmental and inflammatory pathways. Together, these findings establish ACE engineering as a strategy to enhance the production and antimicrobial function of human iPSC-derived neutrophils and support further preclinical development of engineered granulocyte therapies for severe drug-resistant infections.

immunology↗

bioRxiv2026

Tetravalent dengue mRNA vaccination orchestrates balanced four-serotype immunity with durable memory and protection in mice.

An effective dengue vaccine must establish durable immunity across four dengue virus (DENV) serotypes, evade antibody-dependent enhancement (ADE), and overcome immune imprinting from prior exposure. Here, we developed TetprM-E mRNA-LNP, a tetravalent vaccine comprising LNP-formulated nucleoside-modified mRNAs encoding DENV1-4 precursor membrane-envelope (prM-E) antigens, and evaluated its immunogenicity, durability, protection and breath across serotype-specific immune backgrounds. Three immunization strategies elicited neutralizing titers greater than 1:1500 against each serotype. Passive transfer of immune sera conferred 100% survival and reduced viremia after lethal DENV2 challenge in immunocompromised mice. Vaccination induced DENV envelope (env)-specific CD8+T cells and CD4-dependent germinal-center responses. DENV env-binding antibodies persisted for 34 weeks alongside DENV env-specific memory B cells. Vaccine-elicited sera showed no measurable in vitro ADE. Although monovalent priming initially biased antibody responses, TetprM-E mRNA-LNP vaccination broadened neutralization across DENV1-4 regardless of priming serotype. Together, TetprM-E mRNA-LNP elicits broad, durable, and protective immunity despite serologic constraints from pre-existing immunity.

immunology↗