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