S. Downs-Canner1, N. Obermajer1, R. Ravindranathan1, K. Odunsi3, R. Edwards1, P. Kalinski1, D. Bartlett1 1University Of Pittsburgh,Surgical Oncology,Pittsburgh, PA, USA 3Roswell Park Cancer Institute,Gynecologic Oncology,Buffalo, NY, USA
Introduction: To evaluate the role of the Th17 cells in the course of tumor development, we examined the interplay of Th17 and Treg cells. Tumor-infiltrating Th17 cells constitute a prominent part of the cancer microenvironment and are a potent inflammatory subset of T lymphocytes characterized by their signature cytokine IL-17A and their master transcription factor RORγt. While Th17 cells from human or murine tumors appear to favor the early growth of a variety of malignancies by promoting angiogenesis or suppressing tumor immunity, limited studies imply that at later time points, adoptively transferred Th17 cells could mediate durable antitumor responses.
Methods: We used human ascites material to define key subsets of Th17 cells present in ovarian cancer patients. For in depth in vivo mechanistic studies, we used transplantable (ID8-MOSEC and MC-38 cells) and inducible (azoxymethane ± dextran sodium sulfate) tumor models to define the key features of Th17 cell plasticity in the setting of tumor. Further, we evaluated Th17 plasticity in vivo in IL-17aCreRosaeYFP reporter mice which enable fate mapping of cells with highly activated IL-17A, regardless of their IL-17A production at the time of analysis. We determined the impact of Th17 cell plasticity on tumor progression in B6.129P2(Cg)-Rorctm2Litt/J (Rorγ -/-) mice (characterized by RORγ t deficient T cells).
Results: Our data demonstrate increased infiltration of IL17+ and FoxP3+ CD4+ T cells in the human cancer microenvironment, with the presence of a distinct IL17+FoxP3+ subset, and a significant correlation between tumor-associated Th17 and Treg cells in cancer patients. The data in IL-17aCreRosaeYFP reporter mice indicate plasticity between Th17 and Treg cells. Moreover, RORγ t is required not only for Th17 development, but also for effective Treg cell induction. While FoxP3 expression was not induced in ROR-γ -/- cells, TGF-b1 strongly induced FoxP3 expression in control cells. Further, tumor bearing ROR-γ -/- mice showed significantly less FoxP3+ Treg cells, but higher IFNg+ T cells compared to wild type animals.
Conclusion: Tumor development fosters an imbalance in the Th17/Treg ratio, driven by plasticity between the two cell types, both regulated in a RORγt dependent manner. The possibility to control Th17/Treg plasticity and prioritize Th1-like immune responses through manipulation of RORγt offers a novel approach to overcome tumor-associated immunosuppression and enhance clinical effectiveness of anticancer immunotherapy by improving local antitumor activities of CTLs, Th1- and NK cells and preventing dominance and persistence of Treg – governed tumor immunosuppression.