Immunosuppressive effects of melanoma-derived heavy-chain ferritin are dependent on stimulation of IL-10 production

Gray, Christian; Franco, Agustin V.; Arosio, Paolo; Hersey, Peter

doi:10.1002/ijc.1269

Cited by 62 publications

(62 citation statements)

References 51 publications

(42 reference statements)

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“…IL-10 interferes with antitumor immune responses (30,31) and can also inhibit Th1 priming (32,33). In contrast to 2 other reports (11,12), we did not detect increased levels of spontaneous IL-10 secretion by immature B-CLL-DCs when compared with normalDCs (see Figure 2C).…”

Section: Discussioncontrasting

confidence: 97%

Dendritic Cells from Chronic Lymphocytic Leukemia Patients Are Normal Regardless of Ig V Gene Mutation Status

Messmer

Telusma

Wasil

et al. 2004

Mol Med

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Patients with B-type chronic lymphocytic leukemia (B-CLL) segregate into 2 subgroups based on the mutational status of the immunoglobulin (Ig) V genes and the patients in these subgroups follow very different clinical courses. To examine whether dendritic cells (DCs) generated from CLL patients can be candidates for immune therapy, we compared the phenotypic and functional capacities of DCs generated from patients of the 2 CLL subgroups (normal age-matched subjects [normal-DCs]). Our data show that immature DCs from B-CLL patients (B-CLL-DCs) have the same capacity to take up antigen as those from normal controls. Furthermore, B-CLL-DCs generated from the 2 CLL subgroups up-regulated MHC-II, CD80, CD86, CD83, CD40, and CD54 and down-regulated CD206 in response to stimulation with a cocktail of cytokines (CyC) and secreted increased levels of tumor necrosis factor α, interleukin (IL)-8, IL-6, IL-12 (p70), and RANTES in a manner typical of mature normal-DCs. Interestingly, CD54 was significantly more up-regulated by CyC in B-CLL-DCs compared with normal-DCs. Except for CD54, no significant differences in surface molecule expression were observed between normal-DCs and B-CLL-DCs. B-CLL-DCs from both subgroups, including 6 patients with VH1-69, that usually fare poorly, presented tetanus toxoid to autologous T cells in vitro similar to normalDCs. Our data show that DCs generated from the B-CLL subgroup with unmutated Ig V genes are functionally normal. These results are very promising for the use of DCs from patients with poor prognosis for immunotherapy.

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Section: Discussioncontrasting

confidence: 97%

Dendritic Cells from Chronic Lymphocytic Leukemia Patients Are Normal Regardless of Ig V Gene Mutation Status

Messmer

Telusma

Wasil

et al. 2004

Mol Med

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“…Proliferation assays were set up as described by Gray et al 10 Briefly, 1 ϫ 10 5 nonadherent PBLs were cultured with adherent PBMCs or DCs in 200 L DMEM containing 10% FCS (CSL Biosciences) in a 96-well U-bottom plate (Falcon, Becton Dickinson). H-ferritin, L-ferritin, or CD40L was added to the culture at 1 g/mL along with 50 ng/mL anti-CD3.…”

Section: Proliferation Assaymentioning

confidence: 99%

“…Some melanoma cells released predominantly H-ferritin, whereas others contained more equal proportions of H-and L-ferritin. 10 The immunosuppressive effects of the supernatants correlated with their content of Hferritin. These findings were consistent with previous reports that H-ferritin could suppress proliferation of T cells [18][19][20] and E rosette formation.…”

Section: Introductionmentioning

confidence: 97%

“…8,9 We have recently reported that heavy chain ferritin (H-ferritin) appears to be another factor released by melanoma cells that may suppress immune responses by its ability to induce IL-10 production in lymphocytes. 10 Ferritin is a major tissue iron-binding protein 11 and in its native form has a molecular weight of approximately 500 kd. It is composed of 24 subunits consisting of acid/heavy (H) and basic/light (L) chains.…”

Section: Introductionmentioning

confidence: 99%

“…Interferon-␥ (IFN-gamma) production was also increased in lymphocytes exposed to H-ferritin. 10 In the present study we have examined the mechanism by which H-ferritin induces IL-10 production and the cell types in blood responsible for the production of IL-10. We report that H-ferritin appears to mediate its effects on lymphocytes by action on adherent cells and dendritic cells (DCs) generated from monocytes.…”

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confidence: 99%

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Heavy chain ferritin activates regulatory T cells by induction of changes in dendritic cells

Gray

Arosio

Hersey

2002

Blood

Self Cite

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Heavy chain ferritin (H-ferritin) is a component of the iron-binding protein, ferritin. We have previously shown that H-ferritin inhibits anti-CD3-stimulated lymphocyte proliferation and that this was due to increased production of interleukin-10 (IL-10). In the present study we have shown that induction of IL-10 production was due to effects of H-ferritin on adherent antigen-presenting cells ( IntroductionThe growth of melanoma, especially in its more advanced stages, can be associated with suppression of immune responses to the tumor and to other antigens. 1,2 Induction of anergy to melanoma antigens due to lack of costimulatory molecules or production of reactive oxygen metabolites is one possible mechanism for such changes. 3 In addition, a number of soluble factors produced by melanoma cells have been described that down-regulate immune responses via direct effects on lymphocytes or on antigen-presenting cells (APCs) in the vicinity of the tumor (reviewed by Hersey 4 ). Such factors include vascular endothelial growth factor, 5,6 interleukin-10 (IL-10), 7 and transforming growth factor-␤ (TGF-␤). 8,9 We have recently reported that heavy chain ferritin (H-ferritin) appears to be another factor released by melanoma cells that may suppress immune responses by its ability to induce IL-10 production in lymphocytes. 10 Ferritin is a major tissue iron-binding protein 11 and in its native form has a molecular weight of approximately 500 kd. It is composed of 24 subunits consisting of acid/heavy (H) and basic/light (L) chains. 12,13 The genes encoding H-ferritin and light chain ferritin (L-ferritin) are found in different chromosomes and are transcriptionally independent. 14 The 24-subunit polymer may form isoferritins, which are either more acidic (H-rich) or more basic (L-rich) depending on the relative proportions of H and L chains. Liver and spleen ferritins are basic, because they are made up mainly of light chains and very few heavy chains. In contrast, heart, kidney, and placental ferritins are highly acidic, because they are composed mostly of heavy chains. 15 The ferritin found in cancer cells was found to consist mainly of heavy chains. 16,17 Marked variability was found in the ratios of H-to L-ferritin in supernatants from melanoma cultures. Some melanoma cells released predominantly H-ferritin, whereas others contained more equal proportions of H-and L-ferritin. 10 The immunosuppressive effects of the supernatants correlated with their content of Hferritin. These findings were consistent with previous reports that H-ferritin could suppress proliferation of T cells [18][19][20] and E rosette formation. 21 In our previous studies it was found that monoclonal antibodies (mAbs) against H-ferritin or against IL-10 could reverse the immunosuppressive effects. The latter was produced from lymphocytes exposed to H-ferritin and was associated with small decreases in IL-2 and IL-4 production. Interferon-␥ (IFN-gamma) production was also increased in lymphocytes exposed to H-ferritin. 10 In the present study we ha...

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A novel prognostic model based on ferritin and nomogram‐revised risk index could better stratify patients with extranodal natural killer/T‐cell lymphoma

et al. 2023

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Background Extranodal natural killer (NK)/T‐cell lymphoma (ENKTCL) is an aggressive lymphoma with marked heterogeneity, resulting in a distinct prognosis even in patients with the same disease stage. The nomogram‐revised risk index (NRI) has been proposed to stratify patients with ENKTCL. Numerous reports have revealed the prognostic role of serum ferritin in various cancers. Purpose We aimed to evaluate the role of NRI in our single cohort of patients with ENKTCL treated uniformly, explore the prognostic value of ferritin, and establish a new prognostic model to better stratify patients with ENKTCL. Methods We included 326 patients with ENKTCL with detailed data regarding clinical characteristics and survival outcomes. All patients were treated with asparaginase‐based chemotherapy with or without radiotherapy. Multiple R packages were used to analyze the prognostic factors and derive a novel prognostic model. Results In the training cohort comprising 236 patients with ENKTCL, NRI significantly correlated with progression‐free survival (PFS) and overall survival (p < 0.0001). Using a ferritin level of 400 μg/L as the cutoff value, patients with high ferritin levels had significantly inferior PFS (p = 0.00028). Integrating the NRI score and four easily accessible clinical parameters, namely ferritin, hemoglobin, albumin, and D‐dimer, a new prognostic model was constructed, stratifying patients with ENKTCL into three risk groups. This new prognostic model was independent of disease stage and NRI and performed better than NRI. Furthermore, this model helped to stratify patients within the same NRI risk groups. Finally, the role of this novel prognostic model was validated in the external validation cohort comprising 90 patients with ENKTCL. Conclusions Serum ferritin level could be a novel prognostic factor in patients with ENKTCL. The new prognostic model combining NRI and clinical parameters could better predict the prognosis of ENKTCL, thereby warranting further validation and potentially guiding individualized treatment in future prospective clinical trials.

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Immunosuppressive effects of melanoma-derived heavy-chain ferritin are dependent on stimulation of IL-10 production

Cited by 62 publications

References 51 publications

Dendritic Cells from Chronic Lymphocytic Leukemia Patients Are Normal Regardless of Ig V Gene Mutation Status

Dendritic Cells from Chronic Lymphocytic Leukemia Patients Are Normal Regardless of Ig V Gene Mutation Status

Heavy chain ferritin activates regulatory T cells by induction of changes in dendritic cells

A novel prognostic model based on ferritin and nomogram‐revised risk index could better stratify patients with extranodal natural killer/T‐cell lymphoma

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