Regulatory T cell migration and accumulation in tumors and secondary lymphoid tissue during murine 4T1 breast cancer progression 2305484

Abstract

Abstract Introduction Infiltrating regulatory T cells (Tregs) within tumor microenvironments suppress tumor immune responses and are correlated with increased tumor growth. However, the mechanisms regulating distribution of Tregs within tumors or nearby tumor-draining lymph nodes (dLN) is not fully understood. During lymphocyte trafficking, L-selectin functions to regulate migration of lymphocytes to lymph nodes through high endothelial venules (HEV). L-selectin can also mediate lymphocyte trafficking to sites of inflammation by binding to ligands present on inflamed endothelium. Methods Using a murine 4T1 breast cancer model in L-selectin deficient mice (Foxp3EGFP/L-selectin-/- ), Treg cell migration to tumors, draining and non-draining lymphoid tissue during tumor progression was tracked and quantified by flow cytometry. Results Here we demonstrated L-selectin facilitates Treg cell distribution and migration within secondary lymphoid and 4T1 tumor tissue. Treg populations preferentially accumulated in tumor dLNs and increased at higher rates than conventional CD4+ T cell populations during tumor progression. L-selectin deficient mice (Foxp3EGFP/L-selectin-/- ) had significantly reduced numbers of Treg populations within the dLN, ndLN and within tumor tissue. Migration of Tregs into dLNs occurred primarily from the blood through HEV and was L-selectin-dependent. However, Treg cells were also able to enter dLNs from the tumor through afferent lymphatics. In L-selectin deficient mice, Treg cell migration into solid tumor tissue was also reduced during late stage tumors. Conclusion Therefore, these studies demonstrate Treg influx into tumor and dLNs occurs by specific homing of Tregs to these tissues and may be dependent on Treg expression of L-selectin. Funding Source UWM Chancellor’s Office and the UWM Graduate School Research Growth Initiative (RGI) program; UWM Graduate School through an Advanced Opportunity Program (AOP) Fellowship Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)