title: DC-HIL-expressing myelomonocytic cells are critical promoters of melanoma growth.
abstract: A major barrier to successful cancer immunotherapy is the tumor's ability to induce T-cell tolerance by exploiting host regulatory mechanisms. Having discovered the DC-HIL receptor, which inhibits T-cell responses by binding to syndecan-4 on effector T cells, we posited the DC-HIL/syndecan-4 pathway to have an important role in cancer promotion. Among DC-HIL(+) myelomonocytic cells, during growth of implanted mouse melanoma, CD11b(+)Gr1(+) cells were the most expanded population and the most potent at suppressing T-cell activation. Deletion of the DC-HIL gene or infusion of anti-DC-HIL mAb abrogated these cells' suppressor function and expansion, and markedly diminished melanoma growth and metastasis. IL-1β and IFN-γ were elevated in mice bearing melanoma, and concurrent exposure to both cytokines optimally induced DC-HIL expression by tumor-infiltrating CD11b(+)Gr1(+) cells. Ligation of DC-HIL transduced phosphorylation of its intracellular immunoreceptor tyrosine-based activation motif, which in turn induced intracellular expression of IFN-γ and inducible nitric oxide synthase (iNOS), known to mediate T-cell suppression by CD11b(+)Gr1(+) cells. Thus, DC-HIL is the critical mediator of these cells' suppressor function in melanoma-bearing mice and a potential target for improving melanoma immunotherapy.
authors.affiliation: Department of Dermatology, The University of Texas Southwestern Medical Center and Dermatology Section (Medical Service), Dallas Veterans Affairs Medical Center, Dallas, Texas, USA.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Chung
authors.affiliation: Department of Dermatology, The University of Texas Southwestern Medical Center and Dermatology Section (Medical Service), Dallas Veterans Affairs Medical Center, Dallas, Texas, USA.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Department of Dermatology, The University of Texas Southwestern Medical Center and Dermatology Section (Medical Service), Dallas Veterans Affairs Medical Center, Dallas, Texas, USA.
authors.forename: Ponciano D
authors.initials: PD
authors.lastname: Cruz
authors.affiliation: Department of Dermatology, The University of Texas Southwestern Medical Center and Dermatology Section (Medical Service), Dallas Veterans Affairs Medical Center, Dallas, Texas, USA. Electronic address: kiyoshi.ariizumi@utsouthwestern.edu.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ariizumi
mesh_terms: D019264:Adoptive Transfer; D020816:Amino Acid Motifs; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008213:Lymphocyte Activation; D008545:Melanoma / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology*; D009368:Neoplasm Transplantation; D010641:Phenotype; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D053671:Syndecan-4 / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D014443:Tyrosine / Q000737:chemistry
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D053583:Interleukin-1beta; D008562:Membrane Glycoproteins; D053671:Syndecan-4; D014443:Tyrosine; D007371:Interferon-gamma