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DC-HIL+ CD14+ HLA-DR no/low cells are a potential blood marker and therapeutic target for melanoma.

Turrentine J, Chung JS, Nezafati K, Tamura K, Harker-Murray A, Huth J, Sharma RR, Harker DB, Ariizumi K, Cruz PD - J. Invest. Dermatol. (2014)

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.

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Immunosuppression is a potent promoter of cancer progression that not only counters host control of tumor spread but also prevents anti-cancer treatments from achieving their full benefit... Because CD11bGr1 cells are most potent at suppressing T-cell function, their exponential proliferation in cancer patients severely limits efficacy of immunotherapy... We discovered the DC-HIL receptor to potently inhibit effector T-cell function following binding to syndecan-4 (SD-4) on these cells... Interestingly, in the case of one patient (M71), the % DC-HILCD14HLA-DR cells that declined a month post-resection climbed back to a high level at 3 months, which coincided with discovery of a new melanoma in situ (stage 0), and then fell back after resection of this second melanoma... We concluded that melanoma is responsible (directly or indirectly) for acquisition of DC-HIL expression by CD14HLA-DR cells... Do CD14HLA-DR cells from melanoma patients suppress T-cell function and is DC-HIL responsible for that function? CD14HLA-DR cells isolated from melanoma patients (vs. healthy donors) were cocultured with autologous T-cells activated by anti-CD2/CD3/CD28 Ab (Figure 2a)... CD14HLA-DR cells from melanoma patients inhibited IFN-γ production by autologous T-cells dose-dependently and almost completely, whereas corresponding cells from healthy donors were weakly immunosuppressive... Both treatments have been shown to prolong survival of patients with metastatic melanoma, presumably by blocking the inhibitory functions of CTLA-4 and PD-1, respectively... However, their benefits have been limited by development of autoimmune disease causing dermatitis, hepatitis, colitis, and in many cases, death, making the search for even better treatments important... Moreover, both CTLA-4 and PD-1 are expressed by most activated T-cells and regulate development of autoreactive T-cells via regulatory T-cell function... By contrast, SD-4 (the DC-HIL ligand) is expressed by only a restricted population of effector T-cells, with no impact on regulatory T-cell function... In sum, the positive correlation between % blood DC-HILCD14HLA-DR cells and advancing melanoma stage, this parameter’s quick decline after resection of early melanoma, and the restoration by anti-DC-HIL mAb of the T-cell IFN-γ response in melanoma patients constitute strong bases for developing these cells as a useful biomarker and therapeutic target for melanoma... Our results should be confirmed by large, multi-centers studies.

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Anti-DC-HIL mAb treatment restored IFN-γ response in melanoma patients(a) CD14+HLA-DRno/low cells from stage III patient or healthy donor cocultured with T-cells/HLA-DR+ cells (varying ratios) with anti-CD2/CD3/CD28 Ab. (b) Effect of anti-DC-HIL or control IgG on IFN-γ secretion by the coculture (1:1 cell ratio) is expressed as IFN-γ amount (%) relative to T-cell culture: 50 and 53 ng/ml for HD and melanoma, respectively (a); and 24 ng/ml for (b). Representative data of 3 different patients. (c) PBMCs from same patients with stages III/IV were cultured with Ab; fold increase in IFN-γ amounts (mAb vs. IgG) is shown with Pearson’s correlation coefficient r. (d) Same experiments were performed with all samples, and values of fold increase in IFN-γ production plotted to cancer stage. *p<0.001.
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Figure 2: Anti-DC-HIL mAb treatment restored IFN-γ response in melanoma patients(a) CD14+HLA-DRno/low cells from stage III patient or healthy donor cocultured with T-cells/HLA-DR+ cells (varying ratios) with anti-CD2/CD3/CD28 Ab. (b) Effect of anti-DC-HIL or control IgG on IFN-γ secretion by the coculture (1:1 cell ratio) is expressed as IFN-γ amount (%) relative to T-cell culture: 50 and 53 ng/ml for HD and melanoma, respectively (a); and 24 ng/ml for (b). Representative data of 3 different patients. (c) PBMCs from same patients with stages III/IV were cultured with Ab; fold increase in IFN-γ amounts (mAb vs. IgG) is shown with Pearson’s correlation coefficient r. (d) Same experiments were performed with all samples, and values of fold increase in IFN-γ production plotted to cancer stage. *p<0.001.

Mentions: Do CD14+HLA-DRno/low cells from melanoma patients suppress T-cell function and is DC-HIL responsible for that function? CD14+HLA-DRno/low cells isolated from melanoma patients (vs. healthy donors) were cocultured with autologous T-cells activated by anti-CD2/CD3/CD28 Ab (Figure 2a). CD14+HLA-DRno/low cells from melanoma patients inhibited IFN-γ production by autologous T-cells dose-dependently and almost completely, whereas corresponding cells from healthy donors were weakly immunosuppressive.


DC-HIL+ CD14+ HLA-DR no/low cells are a potential blood marker and therapeutic target for melanoma.

Turrentine J, Chung JS, Nezafati K, Tamura K, Harker-Murray A, Huth J, Sharma RR, Harker DB, Ariizumi K, Cruz PD - J. Invest. Dermatol. (2014)

Anti-DC-HIL mAb treatment restored IFN-γ response in melanoma patients(a) CD14+HLA-DRno/low cells from stage III patient or healthy donor cocultured with T-cells/HLA-DR+ cells (varying ratios) with anti-CD2/CD3/CD28 Ab. (b) Effect of anti-DC-HIL or control IgG on IFN-γ secretion by the coculture (1:1 cell ratio) is expressed as IFN-γ amount (%) relative to T-cell culture: 50 and 53 ng/ml for HD and melanoma, respectively (a); and 24 ng/ml for (b). Representative data of 3 different patients. (c) PBMCs from same patients with stages III/IV were cultured with Ab; fold increase in IFN-γ amounts (mAb vs. IgG) is shown with Pearson’s correlation coefficient r. (d) Same experiments were performed with all samples, and values of fold increase in IFN-γ production plotted to cancer stage. *p<0.001.
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Related In: Results  -  Collection

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Figure 2: Anti-DC-HIL mAb treatment restored IFN-γ response in melanoma patients(a) CD14+HLA-DRno/low cells from stage III patient or healthy donor cocultured with T-cells/HLA-DR+ cells (varying ratios) with anti-CD2/CD3/CD28 Ab. (b) Effect of anti-DC-HIL or control IgG on IFN-γ secretion by the coculture (1:1 cell ratio) is expressed as IFN-γ amount (%) relative to T-cell culture: 50 and 53 ng/ml for HD and melanoma, respectively (a); and 24 ng/ml for (b). Representative data of 3 different patients. (c) PBMCs from same patients with stages III/IV were cultured with Ab; fold increase in IFN-γ amounts (mAb vs. IgG) is shown with Pearson’s correlation coefficient r. (d) Same experiments were performed with all samples, and values of fold increase in IFN-γ production plotted to cancer stage. *p<0.001.
Mentions: Do CD14+HLA-DRno/low cells from melanoma patients suppress T-cell function and is DC-HIL responsible for that function? CD14+HLA-DRno/low cells isolated from melanoma patients (vs. healthy donors) were cocultured with autologous T-cells activated by anti-CD2/CD3/CD28 Ab (Figure 2a). CD14+HLA-DRno/low cells from melanoma patients inhibited IFN-γ production by autologous T-cells dose-dependently and almost completely, whereas corresponding cells from healthy donors were weakly immunosuppressive.

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.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Immunosuppression is a potent promoter of cancer progression that not only counters host control of tumor spread but also prevents anti-cancer treatments from achieving their full benefit... Because CD11bGr1 cells are most potent at suppressing T-cell function, their exponential proliferation in cancer patients severely limits efficacy of immunotherapy... We discovered the DC-HIL receptor to potently inhibit effector T-cell function following binding to syndecan-4 (SD-4) on these cells... Interestingly, in the case of one patient (M71), the % DC-HILCD14HLA-DR cells that declined a month post-resection climbed back to a high level at 3 months, which coincided with discovery of a new melanoma in situ (stage 0), and then fell back after resection of this second melanoma... We concluded that melanoma is responsible (directly or indirectly) for acquisition of DC-HIL expression by CD14HLA-DR cells... Do CD14HLA-DR cells from melanoma patients suppress T-cell function and is DC-HIL responsible for that function? CD14HLA-DR cells isolated from melanoma patients (vs. healthy donors) were cocultured with autologous T-cells activated by anti-CD2/CD3/CD28 Ab (Figure 2a)... CD14HLA-DR cells from melanoma patients inhibited IFN-γ production by autologous T-cells dose-dependently and almost completely, whereas corresponding cells from healthy donors were weakly immunosuppressive... Both treatments have been shown to prolong survival of patients with metastatic melanoma, presumably by blocking the inhibitory functions of CTLA-4 and PD-1, respectively... However, their benefits have been limited by development of autoimmune disease causing dermatitis, hepatitis, colitis, and in many cases, death, making the search for even better treatments important... Moreover, both CTLA-4 and PD-1 are expressed by most activated T-cells and regulate development of autoreactive T-cells via regulatory T-cell function... By contrast, SD-4 (the DC-HIL ligand) is expressed by only a restricted population of effector T-cells, with no impact on regulatory T-cell function... In sum, the positive correlation between % blood DC-HILCD14HLA-DR cells and advancing melanoma stage, this parameter’s quick decline after resection of early melanoma, and the restoration by anti-DC-HIL mAb of the T-cell IFN-γ response in melanoma patients constitute strong bases for developing these cells as a useful biomarker and therapeutic target for melanoma... Our results should be confirmed by large, multi-centers studies.

Show MeSH
Related in: MedlinePlus