Using B16F10-OVA+VEGF-Chi lymphangiogenic melanoma model, Gkountidi and Garnier et al. demonstrated that tumoral lymphatic endothelial cells (LECs) upregulate MHC-II in response to IFNγ in the TME and show enhanced proliferation and exogenous antigen capture and processing. Tumoral LECs positively correlated with tumor-infiltrating Tregs, induced TCR signaling, and upregulated genes implicated in Treg suppressive functions. MHC-II deletion in LECs decreased tumor growth, increased tumor-infiltrating effector IFNγ+CD4+ T cells and IFNγ+Granzyme B+CD8+ T cells, and locally impaired the suppressive functions of Tregs in tumors.
Contributed by Shishir Pant
ABSTRACT: Several solid malignancies trigger lymphangiogenesis, facilitating metastasis. Tumor-associated lymphatic vessels significantly contribute to the generation of an immunosuppressive tumor microenvironment (TME). Here, we have investigated the ability of tumoral lymphatic endothelial cells (LECs) to function as MHC class II-restricted antigen-presenting cells in the regulation of antitumor immunity. Using murine models of lymphangiogenic tumors engrafted under the skin, we have shown that tumoral LECs upregulate MHC class II and the MHC class II antigen-processing machinery, and that they promote regulatory T cell (Treg) expansion ex vivo. In mice with LEC-restricted lack of MHC class II expression, tumor growth was severely impaired, whereas tumor-infiltrating effector T cells were increased. Reduction of tumor growth and reinvigoration of tumor-specific T-cell responses both resulted from alterations of the tumor-infiltrating Treg transcriptome and phenotype. Treg suppressive functions were profoundly altered in tumors lacking MHC class II in LECs. No difference in effector T-cell responses or Treg phenotype and functions were observed in tumor-draining lymph nodes, indicating that MHC class II-restricted antigen presentation by LECs was required locally in the TME to confer potent suppressive functions to Tregs. Altogether, our study suggests that MHC class II-restricted antigen-presenting tumoral LECs function as a local brake, dampening T cell-mediated antitumor immunity and promoting intratumoral Treg suppressive functions.