MHC Class II Antigen Presentation by Lymphatic Endothelial Cells in Tumors Promotes Intratumoral Regulatory T cell- Suppressive Functions

Abstract

Several solid malignancies trigger lymphangiogenesis, facilitating metastasis. Tumor-associated lymphatic vessels significantly generate an immunosuppressive tumor microenvironment (TME).

Here, we have investigated the ability of tumoral lymphatic endothelial cells (LEC) 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 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 resulted from tumor-infiltrating Treg transcriptome and phenotype alterations. 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 was 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.

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.

CITA DEL ARTÍCULO Cancer Immunol Res. 2021 Jul;9(7):748-764. doi: 10.1158/2326-6066.CIR-20-0784. Epub 2021 May 5.