A Novel Unconventional Antigen MPD5 Elicits Anti-Tumor Humoral Immune Responses in a Subset of Patients with Polycythemia Vera

Xiong, Zeyu; Liu, E.; Yan, Yaohua; Silver, Richard T.; Yang, Fan; Chen, I. H.; Hodge, I.; Verstovšek, Srđan; Segura, Francisco; Wang, H.; Prchal, Josef T.; Yang, Xiao Feng

doi:10.1177/039463200702000218

Cited by 7 publications

(5 citation statements)

References 23 publications

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“…Our recent report showed that pro-apoptotic protein Bax is highly expressed in Tregs in comparison to that in CD4+CD25-T cells. Removal of Tregs via a Baxdependent apoptosis pathway significantly enhances of anti-self antigen (15,29,(270)(271)(272)(273)(274)(275)(276)(277) immune responses (278). This report has demonstrated for the first time that Treg apoptosis pathway can be therapeutically targeted.…”

Section: Inhibition Of Apc Proteosome Functionmentioning

confidence: 82%

“…Although significant progress has been made, many aspects regarding regulation of Tregs remain to be further defined. No doubt, continuous characterization of the molecular mechanisms underlying Treg survival and homeostasis and the regulatory factors would eventually lead to development of novel therapeutics for autoimmune diseases (14,15,274), tumor immunotherapy (13,29,270,272,273,(275)(276)(277), graft-versus-host-disease (271), stem cell therapy (291), and chronic infectious diseases.…”

Section: Resultsmentioning

confidence: 99%

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Factors regulating apoptosis and homeostasis of CD4+CD25highFOXP3+ regulatory T cells are new therapeutic targets

Yang¹

2008

Front Biosci

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CD4+ CD25(high) Foxp3+ regulatory T cells (Tregs), as an active mechanism of immune suppression, have been targeted due to their tremendous therapeutic potentials to prevent autoimmune diseases, transplant rejection, and to inhibit progression of tumors and chronic viral diseases. In last twelve years, substantial molecular differences between homeostasis of Tregs and that of other subsets of T cells and some factors specific in regulation of Treg survival have been characterized. In this overview we focus on panoramic reviewing of 91 factors, pathways and drugs, both well-characterized and newly defined, regarding the survival and homeostasis of Tregs in the following sections: 2: Tregs, an essential mechanism of immune tolerance; 3: nTregs, aTregs and other regulatory T cells; 4: co-stimulation receptor signaling; 5: innate immunity and Toll-like receptor (TLR) signaling; 6: effects of cytokines and hormones; 7: transcription factors in regulation of Tregs; 8: Treg intracellular signaling pathways; 9: drugs and potential therapeutics; and 10: Treg cell survival and death. We recently reported that removal of Tregs via a Bax-dependent apoptotic pathway significantly enhances anti-self antigen immune responses, which demonstrated for the first time the proof of principle that apoptosis of Tregs is a new therapeutic target. Therefore, continued characterization of Treg apoptosis and homeostasis pathways would further improve our understanding in regulation of immune responses by cytokines, hormones and drugs, and would also lead to development of new therapeutics.

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Section: Inhibition Of Apc Proteosome Functionmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Factors regulating apoptosis and homeostasis of CD4+CD25highFOXP3+ regulatory T cells are new therapeutic targets

Yang¹

2008

Front Biosci

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“…[8][9][10][11][12][13][14] Even after discontinuation of therapy, some patients remain in molecular remission, with a JAK2 mutational burden Ͻ 1%, for years, which corresponds to a profound suppression of clonal myeloproliferation. 12 IFN-␣ is a very potent immune modulator [15][16][17][18] and might be able to "burst" immune surveillance and facilitate a stronger antitumor immune response against the JAK2 mutated clone and thus lead to eradication of tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Increase in circulating CD4+CD25+Foxp3+ T cells in patients with Philadelphia-negative chronic myeloproliferative neoplasms during treatment with IFN-α

Riley

Jensen²,

Brimnes

et al. 2011

Blood

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Recent reports have described complete or major molecular remission in patients with polycythemia vera after long-term treatment with the immunomodulatory agent IFN-␣2. Accordingly, there are reasons to believe that the immune system is a key player in eradicating the JAK2 mutated clone in these patients. Foxp3 ؉ regulatory T cells play a pivotal role in maintaining immune homeostasis and, importantly, preventing immune reactivity to self-antigens; however, their suppressive activity can compromise an effective antitumor immune response, and high frequencies of regulatory T cells in peripheral blood have been reported in both hematologic and solid cancers. We have analyzed the number, phenotype, and function of circulating CD4 ؉ CD25 ؉ Foxp3 ؉ T cells in patients with chronic myeloproliferative neoplasms. Surprisingly, we found a marked expan- IntroductionThe classic Philadelphia-negative chronic myeloproliferative neoplasms-essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF)-are characterized by clonal myeloproliferation, decreased apoptosis of myeloid cells, and progressive myelofibrosis with myeloid metaplasia. The JAK2V617 mutation has a major pathogenetic role, being present in more than 95% of PV patients and approximately half of all patients with ET and PMF. 1-4 A higher mutational burden has been correlated to a more severe clinical phenotype and higher risk of progression to myelofibrosis and leukemic transformation. [5][6][7] Recently, reports have described complete or major molecular remissions in PV patients after long-term (years) treatment with pegylated IFN-␣2. [8][9][10][11][12][13][14] Even after discontinuation of therapy, some patients remain in molecular remission, with a JAK2 mutational burden Ͻ 1%, for years, which corresponds to a profound suppression of clonal myeloproliferation. 12 IFN-␣ is a very potent immune modulator 15-18 and might be able to "burst" immune surveillance and facilitate a stronger antitumor immune response against the JAK2 mutated clone and thus lead to eradication of tumor cells.Foxp3 ϩ regulatory T cells (Tregs) are a specific subset of CD4 ϩ T lymphocytes that play a pivotal role in regulation and maintenance of immune tolerance to self-antigens; however, their inhibitory activity has been shown to compromise antitumor immune responses. 15,[18][19][20] CD4 ϩ Tregs are identified by high expression of surface marker CD25 and the intracellular expression of Foxp3 that is crucial for the induction of a regulatory phenotype. [21][22][23] At present, Foxp3 is thought to be the most specific marker of a regulatory phenotype. Nevertheless, in humans, CD4 ϩ effector T cells (Teffs) can express Foxp3 transiently on activation without possessing suppressive potential. 20,23 Other markers (eg, CD49d and CD45RA) have been suggested to aid in the distinction of Teffs and Tregs. Thus, Miyara et al 23 recently showed the presence of 3 distinct populations of Foxp3-expressing CD4 ϩ T cells based on their expression of CD45RA: CD45 Ϫ Foxp3 low...

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“…Because sLAG possesses a very short half-life, it might augment IgG2a responses if it were administered at later time points during therapy. In the clinic, therapeutic benefit associated with the induction of antitumor humoral responses has been reported (2,43,44). Because the induced antibodies in this study were antigen specific, the enhancement of humoral responses by the combination therapy could potentially contribute to overall therapeutic benefit.…”

Section: Discussionmentioning

confidence: 68%

Lymphocyte Activation Gene-3 Fusion Protein Increases the Potency of a Granulocyte Macrophage Colony-Stimulating Factor–Secreting Tumor Cell Immunotherapy

VanRoey

Triebel³

et al. 2008

Clinical Cancer Research

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Purpose: The purpose of the present study was to evaluate granulocyte macrophage colonystimulating factor (GM-CSF)-secreting tumor cell immunotherapy, which is known to stimulate a potent and long-lasting antigen-specific immune response in combination with lymphocyte activation gene-3 fusion protein (LAG-3Ig), which has been shown to act as an adjuvant for priming T helper type 1and cytotoxicT-cell responses. Experimental Design: Survival and immune monitoring studies were done in the B16 melanoma model. GM-CSF^secreting tumor cell immunotherapy was administered as a single s.c. injection and LAG-3Ig was administered s.c. at the immunotherapy site. Results: The studies reported here show that combining LAG-3Ig with GM-CSF^secreting tumor cell immunotherapy prolonged the survival of tumor-bearing animals compared with animals treated with either therapy alone. Prolonged survival correlated with increased numbers of systemic IFNg-secreting CD8 + Tcells and a significantly increased infiltration of activated effector CD8 + T cells into the tumor. Moreover, an increase in antigen-specific IgG1 humoral responses was detected in serum of animals injected with the combination therapy compared with animals injected with either therapy alone. Conclusion: LAG-3Ig combined with a GM-CSF^secreting tumor cell immunotherapy stimulated both cellular and humoral antitumor immune responses that correlated with prolonged survival in tumor-bearing animals.

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A Novel Unconventional Antigen MPD5 Elicits Anti-Tumor Humoral Immune Responses in a Subset of Patients with Polycythemia Vera

Cited by 7 publications

References 23 publications

Factors regulating apoptosis and homeostasis of CD4+CD25highFOXP3+ regulatory T cells are new therapeutic targets

Factors regulating apoptosis and homeostasis of CD4+CD25highFOXP3+ regulatory T cells are new therapeutic targets

Increase in circulating CD4+CD25+Foxp3+ T cells in patients with Philadelphia-negative chronic myeloproliferative neoplasms during treatment with IFN-α

Lymphocyte Activation Gene-3 Fusion Protein Increases the Potency of a Granulocyte Macrophage Colony-Stimulating Factor–Secreting Tumor Cell Immunotherapy

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