Lymphatic-localized Treg-mregDC crosstalk limits antigen trafficking and restrains anti-tumor immunity

Abstract

The tumor microenvironment (TME) has a significant impact on tumor growth and immunotherapy efficacies. However, the precise cellular interactions and spatial organizations within the TME that drive these effects remain elusive. Using advanced multiplex imaging techniques, we have discovered that regulatory T cells (Tregs) accumulate around lymphatic vessels in the peripheral tumor stroma. This localized accumulation is facilitated by mature dendritic cells enriched in immunoregulatory molecules (mregDCs), which promote chemotaxis of Tregs, establishing a peri-lymphatic Treg-mregDC niche. Within this niche, mregDCs facilitate Treg activation, which in turn restrains the trafficking of tumor antigens to the draining mesenteric lymph nodes, thereby impeding the initiation of anti-tumor adaptive immune responses. Disrupting Treg recruitment to mregDCs inhibits tumor progression. Our study provides valuable insights into the organization of TME and how local crosstalk between lymphoid and myeloid cells suppresses anti-tumor immune responses.

Keywords: antigen trafficking; lymphatics; mregDC; multiplex imaging; regulatory T cells; tumor microenvironment.