Tumor-associated lymphatics upregulate MHC-II to suppress tumor-infiltrating lymphocytes Journal Article
| Authors: | Li, C. Y.; Park, H. J.; Shin, J.; Baik, J. E.; Mehrara, B. J.; Kataru, R. P. |
| Article Title: | Tumor-associated lymphatics upregulate MHC-II to suppress tumor-infiltrating lymphocytes |
| Abstract: | Steady-state lymphatic endothelial cells (LECs) can induce peripheral tolerance by presenting endogenous antigens on MHC class I (MHC-I) molecules. Recent evidence suggests that lymph node LECs can cross-present tumor antigens on MHC-I to suppress tumor-specific CD8+ T cells. Whether LECs can act as immunosuppressive cells in an MHC-II dependent manner in the local tumor microenvironment (TME) is not well characterized. Using murine heterotopic and spontaneous tumor models, we show that LECs in the TME increase MHC-II expression in the context of increased co-inhibitory signals. We provide evidence that tumor lymphatics in human melanoma and breast cancer also upregulate MHC-II compared to normal tissue lymphatics. In transgenic mice that lack LEC-specific MHC-II expression, heterotopic tumor growth is attenuated, which is associated with increased numbers of tumor-specific CD8+ and effector CD4+ T cells, as well as decreased numbers of T regulatory CD4+ cells in the TME. Mechanistically, we show that murine and human dermal LECs can take up tumor antigens in vitro. Antigen-loaded LECs in vitro can induce antigen-specific proliferation of CD8+ T cells but not CD4+ T cells; however, these proliferated CD8+ T cells have reduced effector function in the presence of antigen-loaded LECs. Taken together, our study suggests LECs can act as immunosuppressive cells in the TME in an MHC-II dependent manner. Whether this is a result of direct tumor antigen presentation on MHC-II requires additional investigation. © 2022 by the authors. |
| Keywords: | cd8+ t lymphocyte; tumor associated leukocyte; cd8-positive t-lymphocytes; lymphocytes, tumor-infiltrating; mouse; animal; metabolism; animals; mice; melanoma; tumor antigen; transgenic mouse; mice, transgenic; endothelium cell; endothelial cells; antigen presentation; antigens, neoplasm; hla antigen class 2; cd4+ t lymphocyte; cd4-positive t-lymphocytes; histocompatibility antigens class ii; tumor-infiltrating lymphocytes; tumor microenvironment; humans; human; lymphatic immunomodulation |
| Journal Title: | International Journal of Molecular Sciences |
| Volume: | 23 |
| Issue: | 21 |
| ISSN: | 1422-0067 |
| Publisher: | MDPI |
| Date Published: | 2022-11-01 |
| Start Page: | 13470 |
| Language: | English |
| DOI: | 10.3390/ijms232113470 |
| PUBMED: | 36362253 |
| PROVIDER: | scopus |
| PMCID: | PMC9654328 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2022 -- Source: Scopus |
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