Optimal Population of FoxP3+ T Cells in Tumors Requires an Antigen Priming-Dependent Trafficking Receptor Switch

Abstract

FoxP3⁺ T cells populate tumors and regulate anti-tumor immunity. The requirement for optimal population of FoxP3⁺ regulatory T cells in tumors remains unclear. We investigated the migration requirement and stability of tumor-associated FoxP3⁺ T cells. We found that only memory, but not naïve, FoxP3⁺ T cells are highly enriched in tumors. Almost all of the tumor-infiltrating FoxP3⁺ T cells express Helios, an antigen associated either with thymus-generated FoxP3⁺ T cells or activated T cells in the periphery. The tumor-infiltrating FoxP3⁺ T cells largely lack CD62L and CCR7, two trafficking receptors required for T cell migration into secondary lymphoid tissues. Instead, the tumor infiltrating FoxP3⁺ T cells highly express memory/tumor-associated CCR8 and CXCR4. Antigen priming is required for induction of this trafficking receptor phenotype in FoxP3⁺ T cells and only antigen primed, but not antigen-inexperienced naive, FoxP3⁺ T cells can efficiently migrate into tumors. While the migration of FoxP3⁺ T cells into tumors was a readily detectable event, generation of induced FoxP3⁺ T cells within tumors was unexpectedly inefficient. Genetic marking of current and ex-FoxP3⁺ T cells revealed that tumor-infiltrating FoxP3⁺ T cells are highly stable and do not readily convert back to FoxP3⁻ T cells. Taken together, our results indicate that population of tumors with thymus-generated FoxP3⁺ T cells requires an antigen priming-dependent trafficking receptor switch in lymphoid tissues.