CD4 T cell–activating neoantigens enhance personalized cancer vaccine efficacy

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Abstract

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.

Authors

Amanda L. Huff, Gabriella Longway, Jacob T. Mitchell, Lalitya Andaloori, Emily Davis-Marcisak, Fangluo Chen, Melissa R. Lyman, Rulin Wang, Jocelyn Mathew, Benjamin Barrett, Sabahat Rahman, James Leatherman, Mark Yarchoan, Nilofer S. Azad, Srinivasan Yegnasubramanian, Luciane T. Kagohara, Elana J. Fertig, Elizabeth M. Jaffee, Todd D. Armstrong, Neeha Zaidi