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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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Melanoma induces DC-HIL expression by most potent CD11b+Gr1+ suppressors(a) Splenocytes from B16 melanoma-bearing or tumor-free mice (n=3) were assayed for % DCHIL+ cells in 3 myeloid populations. (b, c) CD11b+Gr1+ (CGr1) cells isolated from mice with (b) or without (c) melanoma were examined for expression of Gr1 and coinhibitory receptors (%). (d) These myeloid cells (increasing cell ratios) were cocultured with CFSE-labeled T-cells activated by anti-CD3/CD28 Ab. T-cell proliferation (%) was determined by FACS (histograms). (e) Purified myeloid cells were examined for T cell-stimulatory capacity. Different numbers of myeloid cells were pulsed with gp100 Ag and added to culture of CD8+ pmel-1 T-cells. Culture of T-cells with Ag served as control (No). T-cell proliferation was measured by 3H-thymidine (TdR) incorporation. *p<0.01.
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Figure 2: Melanoma induces DC-HIL expression by most potent CD11b+Gr1+ suppressors(a) Splenocytes from B16 melanoma-bearing or tumor-free mice (n=3) were assayed for % DCHIL+ cells in 3 myeloid populations. (b, c) CD11b+Gr1+ (CGr1) cells isolated from mice with (b) or without (c) melanoma were examined for expression of Gr1 and coinhibitory receptors (%). (d) These myeloid cells (increasing cell ratios) were cocultured with CFSE-labeled T-cells activated by anti-CD3/CD28 Ab. T-cell proliferation (%) was determined by FACS (histograms). (e) Purified myeloid cells were examined for T cell-stimulatory capacity. Different numbers of myeloid cells were pulsed with gp100 Ag and added to culture of CD8+ pmel-1 T-cells. Culture of T-cells with Ag served as control (No). T-cell proliferation was measured by 3H-thymidine (TdR) incorporation. *p<0.01.

Mentions: We next addressed which DC-HIL-expressing host cells promote melanoma growth. Since DC-HIL is expressed by myelomonocytic cells (Chung et al., 2009), we identified the most expanded DC-HIL+ myeloid population from spleen of mice with melanoma (Figure 2a), which turned out to be CD11b+Gr1+ cells, representing about 10% of splenocytes (vs. CD11c+ DC or F4/80+ macrophages which were about 5% each). Forty percent of splenic CD11b+Gr1+ cells expressed DC-HIL, whereas 20% and 66-73% of these cells were respectively PD-L1+ and CD80/CD86+ (Figure 2b). For CD11b+Gr1+ cells from BM, blood, and the B16 tumor site, DC-HIL expression ranged 27-61% (Supplementary Figure S3a-c). By contrast, CD11b+Gr1+ cells from tumor-free mice did not express DC-HIL (Figure 2c). Thus melanoma induced DC-HIL expression of some CD11b+Gr1+ cells in many organs.


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

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

Melanoma induces DC-HIL expression by most potent CD11b+Gr1+ suppressors(a) Splenocytes from B16 melanoma-bearing or tumor-free mice (n=3) were assayed for % DCHIL+ cells in 3 myeloid populations. (b, c) CD11b+Gr1+ (CGr1) cells isolated from mice with (b) or without (c) melanoma were examined for expression of Gr1 and coinhibitory receptors (%). (d) These myeloid cells (increasing cell ratios) were cocultured with CFSE-labeled T-cells activated by anti-CD3/CD28 Ab. T-cell proliferation (%) was determined by FACS (histograms). (e) Purified myeloid cells were examined for T cell-stimulatory capacity. Different numbers of myeloid cells were pulsed with gp100 Ag and added to culture of CD8+ pmel-1 T-cells. Culture of T-cells with Ag served as control (No). T-cell proliferation was measured by 3H-thymidine (TdR) incorporation. *p<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Melanoma induces DC-HIL expression by most potent CD11b+Gr1+ suppressors(a) Splenocytes from B16 melanoma-bearing or tumor-free mice (n=3) were assayed for % DCHIL+ cells in 3 myeloid populations. (b, c) CD11b+Gr1+ (CGr1) cells isolated from mice with (b) or without (c) melanoma were examined for expression of Gr1 and coinhibitory receptors (%). (d) These myeloid cells (increasing cell ratios) were cocultured with CFSE-labeled T-cells activated by anti-CD3/CD28 Ab. T-cell proliferation (%) was determined by FACS (histograms). (e) Purified myeloid cells were examined for T cell-stimulatory capacity. Different numbers of myeloid cells were pulsed with gp100 Ag and added to culture of CD8+ pmel-1 T-cells. Culture of T-cells with Ag served as control (No). T-cell proliferation was measured by 3H-thymidine (TdR) incorporation. *p<0.01.
Mentions: We next addressed which DC-HIL-expressing host cells promote melanoma growth. Since DC-HIL is expressed by myelomonocytic cells (Chung et al., 2009), we identified the most expanded DC-HIL+ myeloid population from spleen of mice with melanoma (Figure 2a), which turned out to be CD11b+Gr1+ cells, representing about 10% of splenocytes (vs. CD11c+ DC or F4/80+ macrophages which were about 5% each). Forty percent of splenic CD11b+Gr1+ cells expressed DC-HIL, whereas 20% and 66-73% of these cells were respectively PD-L1+ and CD80/CD86+ (Figure 2b). For CD11b+Gr1+ cells from BM, blood, and the B16 tumor site, DC-HIL expression ranged 27-61% (Supplementary Figure S3a-c). By contrast, CD11b+Gr1+ cells from tumor-free mice did not express DC-HIL (Figure 2c). Thus melanoma induced DC-HIL expression of some CD11b+Gr1+ cells in many organs.

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