Origin and Dynamics of Tumor-Associated Foxp3+ Regulatory T Cells (49.4)

Abstract Regulatory T cells (Tregs) expressing the forkhead transcription factor Foxp3 play a central role in the dominant control of immunological tolerance. Compelling evidence obtained from both animal and clinical studies have now linked the expansion and accumulation of Foxp3+ Tregs at the tumor site to the failure of immune-mediated tumor rejection. However, little is known regarding tumor-associated Foxp3+ Tregs within tumor tissues. Using both subcutaneous (s.c.) tumor and lung metastasis models of MCA-205 fibrosarcoma, we have found that tumor-associated Foxp3+ Tregs are highly activated and undergo vigorous cellular proliferation. Tumor-associated Foxp3+ Tregs were also found to be more potent functionally by in-vitro suppression assays and express higher levels of membrane-bound TGF-b1. To visualize endogenous Foxp3+ Tregs, we have generated Foxp3-GFP transgenic reporter mice by inserting GFP into a bacterial artificial chromosome (BAC) encompassing the Foxp3 locus. Using multi-photon microscopy, we observed a rapid recruitment and accumulation of Foxp3+ Tregs to the nascent lung tumor metastasis as early as 3 days after tumor inoculation. Intravital imaging of established s.c. tumors revealed a distinctive behavior of Foxp3+Tregs: the suppressor cells form a well-defined periperipheral layer encasing the tumor mass, moving rapidly within the superficial plain but not perpendicularly in and out of the tumor. Together, these data highlight that tumor-associated Foxp3+ Tregs are highly dynamic in function, behavior, and origin, perhaps contributing to overall poor immunogenicty of tumors.