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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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Infusion of anti-DC-HIL mAb suppresses melanoma growth and expansion of CD11b+Gr1+ cells(a) Tumor volume 6 days after implanting B16 cells into WT mice (n=7), mice injected with anti-DC-HIL mAb or control IgG on indicated days (closed arrows). On days shown by gray arrows in (a), blood taken from mouse, CGr1 cells counted from PBMCs by FACS (b), and data summarized (c). (d) A day after 3 injections, IFN-γ-secreting cells in spleen or LN in each mouse (n=3) counted as number per 1 × 104 cells. (e) Tumor volume on mice treated with the 2 Abs 11 days after implanting KD-B16 cells (n=7). (f) Tumor volume on DCHIL−/− mice treated with Ab 7 days after co-injection of B16 and CGr1 cells. *p<0.001.
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Figure 5: Infusion of anti-DC-HIL mAb suppresses melanoma growth and expansion of CD11b+Gr1+ cells(a) Tumor volume 6 days after implanting B16 cells into WT mice (n=7), mice injected with anti-DC-HIL mAb or control IgG on indicated days (closed arrows). On days shown by gray arrows in (a), blood taken from mouse, CGr1 cells counted from PBMCs by FACS (b), and data summarized (c). (d) A day after 3 injections, IFN-γ-secreting cells in spleen or LN in each mouse (n=3) counted as number per 1 × 104 cells. (e) Tumor volume on mice treated with the 2 Abs 11 days after implanting KD-B16 cells (n=7). (f) Tumor volume on DCHIL−/− mice treated with Ab 7 days after co-injection of B16 and CGr1 cells. *p<0.001.

Mentions: We next assessed effects of the mAb on melanoma growth and frequency of CD11b+Gr1+ cells in blood. Because these cells begin to accumulate in spleen 6 days after tumor inoculation (when tumors reach ~0.1 cm3) (Cheng et al., 2008), we injected anti-DC-HIL mAb i.p. then and every other day, for 6 treatments. In mice treated with control IgG, melanoma grew aggressively, in proportion to frequency of blood CD11b+Gr1+ cells. The mAb markedly suppressed subsequent melanoma growth (Figure 5a) and prevented expansion of CD11b+Gr1+ cells in blood (Figures 5b and c): the latter effect was supported by inability of KO mice to expand CD11b+Gr1+ cells (Supplementary Figure S7). It also significantly enhanced the IFN-γ response by T-cells from mice with melanoma (Figure 5d). Blocked expansion may be due to reduced tumor size with less secretion of relevant soluble factors.


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

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

Infusion of anti-DC-HIL mAb suppresses melanoma growth and expansion of CD11b+Gr1+ cells(a) Tumor volume 6 days after implanting B16 cells into WT mice (n=7), mice injected with anti-DC-HIL mAb or control IgG on indicated days (closed arrows). On days shown by gray arrows in (a), blood taken from mouse, CGr1 cells counted from PBMCs by FACS (b), and data summarized (c). (d) A day after 3 injections, IFN-γ-secreting cells in spleen or LN in each mouse (n=3) counted as number per 1 × 104 cells. (e) Tumor volume on mice treated with the 2 Abs 11 days after implanting KD-B16 cells (n=7). (f) Tumor volume on DCHIL−/− mice treated with Ab 7 days after co-injection of B16 and CGr1 cells. *p<0.001.
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Figure 5: Infusion of anti-DC-HIL mAb suppresses melanoma growth and expansion of CD11b+Gr1+ cells(a) Tumor volume 6 days after implanting B16 cells into WT mice (n=7), mice injected with anti-DC-HIL mAb or control IgG on indicated days (closed arrows). On days shown by gray arrows in (a), blood taken from mouse, CGr1 cells counted from PBMCs by FACS (b), and data summarized (c). (d) A day after 3 injections, IFN-γ-secreting cells in spleen or LN in each mouse (n=3) counted as number per 1 × 104 cells. (e) Tumor volume on mice treated with the 2 Abs 11 days after implanting KD-B16 cells (n=7). (f) Tumor volume on DCHIL−/− mice treated with Ab 7 days after co-injection of B16 and CGr1 cells. *p<0.001.
Mentions: We next assessed effects of the mAb on melanoma growth and frequency of CD11b+Gr1+ cells in blood. Because these cells begin to accumulate in spleen 6 days after tumor inoculation (when tumors reach ~0.1 cm3) (Cheng et al., 2008), we injected anti-DC-HIL mAb i.p. then and every other day, for 6 treatments. In mice treated with control IgG, melanoma grew aggressively, in proportion to frequency of blood CD11b+Gr1+ cells. The mAb markedly suppressed subsequent melanoma growth (Figure 5a) and prevented expansion of CD11b+Gr1+ cells in blood (Figures 5b and c): the latter effect was supported by inability of KO mice to expand CD11b+Gr1+ cells (Supplementary Figure S7). It also significantly enhanced the IFN-γ response by T-cells from mice with melanoma (Figure 5d). Blocked expansion may be due to reduced tumor size with less secretion of relevant soluble factors.

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