J. I. Kim1, D. Daley1, B. Aykut1, J. Gutierrez1, R. Abengozar1, P. Preiss1, R. Chen1, D. Wu1, S. Shadaloey1, A. Ochi1, G. Miller1 1New York University School Of Medicine,Surgery,New York, NY, USA
Introduction:
Pancreatic ductal adenocarcinoma (PDA) is a devastating disease with a high morality burden. Tumor progression in PDA is driven by activation of the innate and adaptive immune responses, and it is well established that innate immune cell subsets within the tumor microenvironment (TME) entrain adaptive immune effector cells towards a tumor-permissive phenotype. However, the key drivers of immune-suppressive monocytic cell differentiation have not been previously elucidated.
Dectin-1, a pattern recognition receptor expressed on the surface of dendritic cells, macrophages, and inflammatory monocytes, has been identified as a means by which the innate immune system recognizes fungal cell wall components. Our preliminary experiments showed high Dectin-1 expression as well as novel Dectin-1 agonists in the PDA TME. We therefore hypothesized that immune-suppressive cell differentiation and PDA infiltration is driven by Dectin-1 ligation in antigen-presenting cells (APCs), which in turn drives the degree of oncogenic progression in genetically susceptible individuals.
Methods:
We investigated the effects of Dectin-1 ligation using both a slowly progressive authochthonous PDA model (KC and KC;Dectin-1-/-) and an orthotopic PDA tumor model in wild-type versus Dectin-1-/- mice. During tumorigenesis, mice were serially treated with Dectin-1 specific ligand depleted Zymosan (d-Zymosan) or heat-killed candida albicans (HKCA). Cellular characteristics of the pancreatic tumor microenvironment unique to Dectin-1 ligation or Dectin-1 absence were analyzed via various methods.
Results:
Dectin-1 was more highly expressed in tumor cells and tumor-infiltrating myeloid cells in the PDA TME of both KC mice and within orthotopic KPC tumors. Furthermore, ligation of Dectin-1 via serial d-Zyosan or HKCA treatments accelerated tumorigenesis in KC mice versus vehicle-treated controls, as well as in orthotopically implanted KPC-derived tumors. Dectin-1 deletion in KC mice also delayed malignant progression, reduced pancreatic tumor weights, and extended median survival by ~5 months. At the cellular level, both KC;Dectin-1-/- pancreata and orthotopic KPC tumor-bearing Dectin-1-/- mice showed ~50% reduction in tumor-associated macrophages versus their respective controls. Additionally, cellular phenotyping of Dectin-1-/- TAMs expressed higher MHC-II and TNF-a, as well as decreased CD206 compared with their Dectin-1+/+ counterparts, suggestive of immunogenic reprogramming towards M1-like differentiation induced by Dectin-1 deletion.
Conclusion:
In PDA, Dectin-1 ligation and, conversely, the absence of Dectin-1 drive differential tumor progression. Furthermore, in the PDA TME, Dectin-1 signaling pays a key role in reprogramming macrophages towards an immune-suppressive versus immunogenic phenotypes, which carries great promise for potential immunotherapies.