Amanda L. Huff; Gabriella Longway; Jacob T. Mitchell; Lalitya Andaloori; Emily F. Davis-Marcisak; Fangluo Chen; Melissa R. Lyman; Rulin Wang; Jocelyn Mathew; Benjamin Barrett; Sabahat Rahman; James M. Leatherman; Mark Yarchoan; Nilofer S. Azad; Srinivasan Yegnasubramanian; Luciane T. Kagohara; Elana J. Fertig; Elizabeth M. Jaffee; Todd D. Armstrong; Neeha Zaidi · 2023 · JCI Insight
Paper
Personalized cancer vaccines aim to activate and expand cytotoxic antitumor CD8+ T cells to recognize and kill tumor cells. However, the role of CD4+ T cell activation in the clinical benefit of these vaccines is not well defined. We previously established a personalized neoantigen vaccine (PancVAX) for the pancreatic cancer cell line Panc02, which activates tumor-specific CD8+ T cells but required combinatorial checkpoint modulators to achieve therapeutic efficacy. To determine the effects of neoantigen-specific CD4+ T cell activation, we generated a vaccine (PancVAX2) targeting both major histocompatibility complex class I- (MHCI-) and MHCII-specific neoantigens. Tumor-bearing mice vaccinated with PancVAX2 had significantly improved control of tumor growth and long-term survival benefit without concurrent administration of checkpoint inhibitors. PancVAX2 significantly enhanced priming and recruitment of neoantigen-specific CD8+ T cells into the tumor with lower PD-1 expression after reactivation compared with the CD8+ vaccine alone. Vaccine-induced neoantigen-specific Th1 CD4+ T cells in the tumor were associated with decreased Tregs. Consistent with this, PancVAX2 was associated with more proimmune myeloid-derived suppressor cells and M1-like macrophages in the tumor, demonstrating a less immunosuppressive tumor microenvironment. This study demonstrates the biological importance of prioritizing and including CD4+ T cell-specific neoantigens for personalized cancer vaccine modalities.
Analysis
This study demonstrates that including CD4 T cell-activating neoantigens in personalized cancer vaccines significantly improves therapeutic efficacy by enhancing CD8 T cell responses and modulating the tumor microenvironment.
Discovery
Vladimir Zyrin; Evgeniy Mozheiko; Ivan Valiev; Alexey Lazarev; Tigran Gevorkyan; Matvey Murashko; Konstantin Okonechnikov
Ashling Cannon
Dinghai Zheng; Justin Hong; Jun Wang; Adrien Villain; Mickaël Costallat; Fernando Ulloa Montoya; Vikram Agarwal
Petar Brlek; Jan Kolić; Luka Bulić; Vedrana Škaro; Dragan Primorac
Almohanad A. Alkayyal
Crodel CC; Gork L; Göpel W; Linke P; Sinn K; Miethke J; Hochhaus A; Hilgendorf I
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