MHC class II antigen presentation by tumoral lymphatics is required for tumor specific signature and suppressive functions of Tregs

A number of solid malignancies triggers lymphangiogenesis, facilitating metastasis. Recent studies further indicate that tumor-associated lymphatic vessels significantly contribute to the generation of an immunosuppressive tumor microenvironment. Here, we have investigated the ability of tumor-associated lymphatic endothelial cells (LECs) to function as MHC class II restricted antigen-presenting cells in the regulation of anti-tumor immunity. Using murine models of lymphangiogenic tumors engrafted under the skin, we show that tumor LECs upregulate MHCII and the MHCII antigen processing machinery, and promote Treg expansion ex vivo. Using mice with a LEC-restricted lack of MHCII expression, we demonstrate that tumor growth is severely impaired, whereas tumor-infiltrating T effector cells are increased. Reduction of tumor growth and reinvigoration of tumor-specific T cell responses both result from alterations of the tumor-infiltrating regulatory T cell (Treg) transcriptome and phenotype. Treg suppressive functions are consequently profoundly altered in tumors lacking MHCII in LECs. No difference in effector T cell responses or Treg phenotype and functions were observed in tumor-draining lymph nodes, indicating that MHCII restricted antigen presentation by LECs is required locally in the tumor microenvironment (TME) to confer potent suppressive functions to Tregs. Altogether, our study advocates a role for MHCII-restricted antigen-presenting tumor LECs that function as a local brake, dampening tumor T cell immunity and promoting intratumoral Treg suppressive functions.