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DC-HIL-expressing myelomonocytic cells are critical promoters of melanoma growth.

Chung JS, Tamura K, Cruz PD, Ariizumi K - J. Invest. Dermatol. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, The University of Texas Southwestern Medical Center and Dermatology Section (Medical Service), Dallas Veterans Affairs Medical Center, Dallas, Texas, USA.

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.

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DC-HIL mediates T cell-suppressor activity of CD11b+Gr1+ cells(a, b) CGr1 cells from melanoma-bearing mice were cocultured with pmel-1 splenocytes (Spl), gp100 Ag, and anti-DC-HIL mAb (a), anti-coinhibitor Ab or control IgG (b). 3H-TdR incorporation measured. (c) Undepleted (DC-HIL+) or DC-HIL-depleted (DC-HILneg) CGr1 (Supplementary method) were assayed for suppression of pmel-1 splenocyte proliferation triggered by Ag (increasing ratios). (d) Mice (n=5) injected with pmel-1 CD8+ T-cells and DC-HIL+CGr1 or DC-HILnegCGr1. Ten days after giving gp100, IFN-γ-producing cells in LN were counted. (e) Tumor growth following coinjection of DC-HIL+ or DC-HILneg CGr1 cells with B16 cells s.c. into naive mice (n=5). Using similar methods, DC-HIL−/−CGr1 cells were compared with DCHIL+/+ counterparts for DC-HIL expression by FACS (f), T-cell suppressing (g) and tumor-promoting ability (CD11bneg cells as control) (h). *p<0.01.
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Figure 3: DC-HIL mediates T cell-suppressor activity of CD11b+Gr1+ cells(a, b) CGr1 cells from melanoma-bearing mice were cocultured with pmel-1 splenocytes (Spl), gp100 Ag, and anti-DC-HIL mAb (a), anti-coinhibitor Ab or control IgG (b). 3H-TdR incorporation measured. (c) Undepleted (DC-HIL+) or DC-HIL-depleted (DC-HILneg) CGr1 (Supplementary method) were assayed for suppression of pmel-1 splenocyte proliferation triggered by Ag (increasing ratios). (d) Mice (n=5) injected with pmel-1 CD8+ T-cells and DC-HIL+CGr1 or DC-HILnegCGr1. Ten days after giving gp100, IFN-γ-producing cells in LN were counted. (e) Tumor growth following coinjection of DC-HIL+ or DC-HILneg CGr1 cells with B16 cells s.c. into naive mice (n=5). Using similar methods, DC-HIL−/−CGr1 cells were compared with DCHIL+/+ counterparts for DC-HIL expression by FACS (f), T-cell suppressing (g) and tumor-promoting ability (CD11bneg cells as control) (h). *p<0.01.

Mentions: CD11b+Gr1+ cells from melanoma-bearing mice were cocultured with pmel-1 splenocytes and gp100 peptide at a 1:1 cell ratio; anti-DC-HIL mAb or control IgG was added to block DC-HIL on CD11b+Gr1+ cells (Figure 3a). The mAb (but not control) restored pmel-1 T-cell activation dose-dependently and completely, but had no effect on T-cell activation without CD11b+Gr1+ cells. Anti-CD80, anti-CD86, or anti-PD-L1 Ab had no significant effect on CD11b+Gr1+ cells’ suppressor activity (Figure 3b). Thus among coinhibitors tested, DC-HIL was responsible solely for suppressor activity of CD11b+Gr1+ cells.


DC-HIL-expressing myelomonocytic cells are critical promoters of melanoma growth.

Chung JS, Tamura K, Cruz PD, Ariizumi K - J. Invest. Dermatol. (2014)

DC-HIL mediates T cell-suppressor activity of CD11b+Gr1+ cells(a, b) CGr1 cells from melanoma-bearing mice were cocultured with pmel-1 splenocytes (Spl), gp100 Ag, and anti-DC-HIL mAb (a), anti-coinhibitor Ab or control IgG (b). 3H-TdR incorporation measured. (c) Undepleted (DC-HIL+) or DC-HIL-depleted (DC-HILneg) CGr1 (Supplementary method) were assayed for suppression of pmel-1 splenocyte proliferation triggered by Ag (increasing ratios). (d) Mice (n=5) injected with pmel-1 CD8+ T-cells and DC-HIL+CGr1 or DC-HILnegCGr1. Ten days after giving gp100, IFN-γ-producing cells in LN were counted. (e) Tumor growth following coinjection of DC-HIL+ or DC-HILneg CGr1 cells with B16 cells s.c. into naive mice (n=5). Using similar methods, DC-HIL−/−CGr1 cells were compared with DCHIL+/+ counterparts for DC-HIL expression by FACS (f), T-cell suppressing (g) and tumor-promoting ability (CD11bneg cells as control) (h). *p<0.01.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199867&req=5

Figure 3: DC-HIL mediates T cell-suppressor activity of CD11b+Gr1+ cells(a, b) CGr1 cells from melanoma-bearing mice were cocultured with pmel-1 splenocytes (Spl), gp100 Ag, and anti-DC-HIL mAb (a), anti-coinhibitor Ab or control IgG (b). 3H-TdR incorporation measured. (c) Undepleted (DC-HIL+) or DC-HIL-depleted (DC-HILneg) CGr1 (Supplementary method) were assayed for suppression of pmel-1 splenocyte proliferation triggered by Ag (increasing ratios). (d) Mice (n=5) injected with pmel-1 CD8+ T-cells and DC-HIL+CGr1 or DC-HILnegCGr1. Ten days after giving gp100, IFN-γ-producing cells in LN were counted. (e) Tumor growth following coinjection of DC-HIL+ or DC-HILneg CGr1 cells with B16 cells s.c. into naive mice (n=5). Using similar methods, DC-HIL−/−CGr1 cells were compared with DCHIL+/+ counterparts for DC-HIL expression by FACS (f), T-cell suppressing (g) and tumor-promoting ability (CD11bneg cells as control) (h). *p<0.01.
Mentions: CD11b+Gr1+ cells from melanoma-bearing mice were cocultured with pmel-1 splenocytes and gp100 peptide at a 1:1 cell ratio; anti-DC-HIL mAb or control IgG was added to block DC-HIL on CD11b+Gr1+ cells (Figure 3a). The mAb (but not control) restored pmel-1 T-cell activation dose-dependently and completely, but had no effect on T-cell activation without CD11b+Gr1+ cells. Anti-CD80, anti-CD86, or anti-PD-L1 Ab had no significant effect on CD11b+Gr1+ cells’ suppressor activity (Figure 3b). Thus among coinhibitors tested, DC-HIL was responsible solely for suppressor activity of CD11b+Gr1+ cells.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, The University of Texas Southwestern Medical Center and Dermatology Section (Medical Service), Dallas Veterans Affairs Medical Center, Dallas, Texas, USA.

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.

Show MeSH
Related in: MedlinePlus