Abstract PO-017: Targeting NF-kB pathway through IRAK4 renders immune checkpoint blockade effective in pancreatic cancer

Effective immunotherapy in pancreatic ductal adenocarcinoma (PDAC) is impeded by multiple barriers in the tumor microenvironment. These include the dense extracellular matrix (ECM), excessive inhibitory myeloid cells, cytokines and chemokines, which collectively incapacitate anti-tumour T cells. Constitutive activation the NF-kB pathway is a mechanism that drives intrinsic survival of PDAC cells and stromal fibrosis, but its impact on anti-tumour immunity has not been investigated. Using The Cancer Genome Atlas database, we found that expression of RELA, a canonical NF-kB factor, in PDAC samples is associated with activated stroma and lower cytotoxic T cell signatures. In a PDAC tissue microarray, the staining intensity of activated IRAK4, the innate immune kinase that drives NF-kB signaling, negatively correlates with T cell abundance. Based on these findings, we investigated the immunological impact role of IRAK4 in PDAC. Transcriptomic analysis showed that ablation of IRAK4 in PDAC cells downregulates NF-kB and inflammatory signatures, and markedly decreases transcription of hyaluronan synthase 2 (HAS2). Accordingly, pharmacologic inhibition of IRAK4 significantly decreased intratumoral hyaluronan, as well as collagen, in autochthonous PDAC mice and potentiated standard chemotherapy. Furthermore, IRAK4 inhibition also significantly reduced production of several suppressive chemokines and checkpoint ligands PD-L1 and Nectin2, leading to revitalization of infiltrative CD4+ and CD8+ T cells. These effects were partly mediated through reduction of intratumoural hyaluronan, which we recapitulated with HAS inhibitor, 4-MU. Accordingly, combined IRAK4 inhibitors with immune checkpoint blockade (ICB) especially anti-CTLA4, were highly efficacious in abrogating tumour growth in autochthonous PDAC mice and doubling their survival. In summary, we showed that targeting the NF-kB pathway through IRAK4 renders ICB effective via multiple mechanisms and should be tested in clinical trials for PDAC patients. Citation Format: Daoxiang Zhang, Vikas Somani, Paarth B. Dodhiawala, Patrick M. Grierson, Lin Li, Kuljeet Seehra, Xiuting Liu, Brett L. Knolhoff, Marianna B. Ruzinova, David G. DeNardo, Kian-Huat Lim. Targeting NF-kB pathway through IRAK4 renders immune checkpoint blockade effective in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-017.