J. I. Kim1, W. Wang1, S. Savadkar1, Y. Wu1, M. Khan1, N. Wu1, W. Su1, J. Wu1, J. Gutierrez1, B. Aykut1, G. Miller1 1New York University School Of Medicine,Surgery,New York, NY, USA
Introduction:
Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer death in the United States, with a mortality rate that approaches its incidence rate (Yadav and Lowenfels, 2013). PDA is characterized by a T cell infiltrate whose terminal differentiation can determine disease outcome by either preventing cancer growth via a tumoricidal immune response, or by driving tumor progression via the induction of immune tolerance. The phenotype of tumor-associated macrophages (TAMs) largely determines immunogenic or immune-suppressive T cell reprogramming in PDA, however the regulators of macrophage polarization in PDA remain unknown.
Receptor-interacting serine/threonine-protein kinase 1 (RIP1) is a serine/threonine protein kinase that drives NF-kB and MAP kinase signaling in response to inflammation and a putative master upstream regulator of TLR signaling. We postulated that RIP1 influences suppressive macrophage polarization in cancer.
Methods:
We synthesized a novel, highly selective, small molecule RIP1 inhibitor with high potency, specificity, and sustained in vivo bioavailability. Using both an orthotopic PDA tumor model and slowly progressive authochthonous PDA model in conjunction with RIP1 inhibitor and in a kinase-dead RIP1 allele transgenic mouse, we investigated the effects of RIP1 signal inhibition in macrophages on innate and adaptive immune tolerance in PDA.
Results:
In an orthotopic tumor model, RIP1i administration reduced tumor burden and extended survival compared to controls, even when administered after tumor establishment. In a slowly progressive authochthonous PDA model, RIP1i-treated KC mice showed delayed development of pancreatic dysplasia, decreased peri-tumoral fibrosis, smaller tumors, and extended survival. RIP1i treatment decreased TAM infiltration of orthotopic KPC tumors by 40%, and reprogrammed TAMs towards a more immunogenic M1-like phenotype characterized by upregulation of MHC-II, CD86, CD80, TNFa, and IFNg. Similar M1-like programming was exhibited by TAMs in RIP1 KD/KI mice.
Conclusion:
In the setting of PDA, RIP1 inhibition confers marked tumor protection via RIP1i promotion of STAT1-dependent immunogenic macrophage polarization. RIP1 inhibition in macrophages furthermore renders T cells indispensable for tumor protection and enables efficacy of both ICOS- and PD-1 based immunotherapies.
RIP1 signaling in macrophages is a master regulator of immune tolerance in PDA and confers resistance to both checkpoint and costimulatory receptor-based immunotherapy. Conversely, RIP1 inhibition reverses intra-tumor immune-suppression, extends survival, and enables efficacy for immunotherapy.