Th138 - Tumor-Infiltrating Regulatory T Cells Are Thymus-Derived

Abstract Text: The presence of FoxP3 regulatory T cells (Treg) in the tumor microenvironment has been associated with poor clinical outcomes. However, the nature of the infiltrating Tregs, particularly whether they represent thymic-derived Tregs or CD4 T cells that undergo a Treg differentiation process locally, remains an open question. The aim of this work was to determine whether CD4 T cells specific to a tumor-derived antigen become FoxP3+ Tregs in the tumor microenvironment or in tumor draining lymph nodes.
B16 murine melanoma cells that expressed ovalbumin (B16-OVA) or not (B16) were inoculated into CD45.1+ wild-type B6 mice. Naïve CD4+ CD45.2+ Foxp3GFP OT-II cells (specific for OVA) were adoptively transferred. CD4 T cell migration into the tumor and tumor draining lymph nodes was analyzed. FoxP3 expression in transferred OVA-specific cells was quantified.
Migration of adoptively transferred OT-II cells into the tumor was negligible, disregarding whether the tumor expressed OVA or not. Virtually all FoxP3 CD4 T cells found in the tumor represented endogenous Helios+ thymic-derived Tregs. OT-II cells recovered from tumor draining lymph nodes were mostly FoxP3 negative. These results were not affected by the capacity of the mouse or the tumor to produce TGF-beta.
These results suggest that the regulatory T cells that infiltrate murine melanoma are thymic-derived and that local differentiation of FoxP3+ regulatory T cells from naïve CD4 T cells is negligible, even when CD4 T cells express a TCR able to recognize a tumor-derived antigen with high affinity.