IL-15 complex enhances therapeutic efficacy of anti-PD-L1 in a T cell–dependent and NK cell–independent manner in a murine model of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy resistant to therapy including immune checkpoint blockade (ICB). We previously showed that ICB selects for pancreatic tumor cells that are defective in IFN-γ-inducible MHC-I, prompting us to test the impact of IL-15 complex (IL-15C) in overcoming ICB resistance. Here, we show that IL-15C markedly expands circulating NK cells, CD8+ T cells, and CD4+Cxcr3+ T cells in an orthotopic pancreatic ductal adenocarcinoma (PDA) animal model. In tumors, IL-15C + anti-PD-L1 increased CD8+ T-cell effector cytokine production and interfered with T-cell exhaustion, including mitigating IL-10. In NK cells, IL-15C + anti-PD-L1 modulated NK cell IFN-γ production but did not alter Nkg2d, Nkg2a, Klrg1, IL-10, or granzyme B. IL-15C + anti-PD-L1 significantly prolonged animal survival, leading to tumor eradication in a subset of animals, whereas monotherapies only transiently prolonged survival. Therapeutic benefit was dependent on CD8+ T cells and independent of NK cells and Nkg2d. Together, our study supports that IL-15C improves anti-PD-L1 in PDA through sustaining antitumor T-cell function.