Functional Cellular Anti-Tumor Mechanisms are Augmented by Genetic Proteoglycan Targeting
| Autor: | Roland El Ghazal, So Young Kim, Scott C. Johns, Purva Gupta, Mark M. Fuster, Elina I. Zuniga |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
CD4-Positive T-Lymphocytes Cancer Research T-Lymphocytes Ova Ovalbumin CD8-Positive T-Lymphocytes Major Histocompatibility Complex chemistry.chemical_compound Carcinoma Lewis Lung Mice 0302 clinical medicine HS Heparan sulfate Loss of Function Mutation Cytotoxic T cell HSPG Heparan sulfate proteoglycan LysM M Lysozyme locus LPS Lipopolysaccharide Immunity Cellular biology Chemistry Heparan sulfate Treg Regulatory T cell lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens DC Dendritic cell 3. Good health medicine.anatomical_structure 030220 oncology & carcinogenesis Proteoglycans Sulfotransferases Original article T cell Clinical Sciences Antigen presentation TIL Tumor Infiltrating Lymphocyte Major histocompatibility complex lcsh:RC254-282 TcR T cell receptor 03 medical and health sciences Sdc Syndecan Immune system Lymphocytes Tumor-Infiltrating Antigen Polysaccharides medicine CD11c CD11c locus Animals Humans Oncology & Carcinogenesis MHC Major histocompatibility complex Histocompatibility Antigens Class I BMDCs Bone marrow dendritic cells Dendritic Cells Molecular biology CD11c Antigen 030104 developmental biology Ndst N-deacetylase/N-sulfotransferase biology.protein LLC Lewis lung carcinoma SIINFEKL Ova peptide sequence for Ova257 Ova264 Heparitin Sulfate CD8 |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 22, Iss 2, Pp 86-97 (2020) Neoplasia (New York, N.Y.) Neoplasia (New York, N.Y.), vol 22, iss 2 |
| ISSN: | 1476-5586 |
| Popis: | While recent research points to the importance of glycans in cancer immunity, knowledge on functional mechanisms is lacking. In lung carcinoma among other tumors, anti-tumor immunity is suppressed; and while some recent therapies boost T-cell mediated immunity by targeting immune-checkpoint pathways, robust responses are uncommon. Augmenting tumor antigen-specific immune responses by endogenous dendritic cells (DCs) is appealing from a specificity standpoint, but challenging. Here, we show that restricting a heparan sulfate (HS) loss-of-function mutation in the HS sulfating enzyme Ndst1 to predominantly conventional DCs (Ndst1f/f CD11cCre+ mutation) results in marked inhibition of Lewis lung carcinoma growth along with increased tumor-associated CD8+ T cells. In mice deficient in a major DC HS proteoglycan (syndecan-4), splenic CD8+ T cells showed increased anti-tumor cytotoxic responses relative to controls. Studies examining Ndst1f/f CD11cCre + mutants revealed that mutation was associated with an increase in anti-tumor cytolysis using either splenic CD8+ T cells or tumor-infiltrating (TIL) CD8+ T cells purified ex-vivo, and tested in pooled effector-to-target cytolytic assays against tumor cells from respective animals. On glycan compositional analysis, HS purified from Ndst1f/f CD11cCre + mutant DCs had reduced overall sulfation, including reduced sulfation of a tri-sulfated disaccharide species that was intriguingly abundant on wildtype DC HS. Interestingly, antigen presentation in the context of major histocompatibility complex class-I (MHC-I) was enhanced in mutant DCs, with more striking effects in the setting of HS under-sulfation, pointing to a likely regulatory role by sulfated glycans at the antigen/MHC-I - T-cell interface; and possibly future opportunities to improve antigen-specific T cell responses by immunologic targeting of HS proteoglycans in cancer. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|