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

Abstract

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...

Correlation between frequencies of blood monocytic myeloid-derived suppressor cells, regulatory T cells and negative prognostic markers in patients with castration-resistant metastatic prostate cancer

“…Thus, we defined Tregs based on these surface markers (Fig. 4a), which we have previously demonstrated possess regulatory capacity [17]. We found significantly higher frequencies of circulating Tregs in patients with PC when compared to healthy donors (P < 0.05 Fig.…”

Divergent effects of type-I interferons on regulatory T cells

“…Another study has confirmed the increase of Treg, enumerated in the peripheral blood by flow cytometry as CD4+ FOXP3+ CD25high cells, in patients with chronic myeloproliferative disorders, treated with peg-IFN-a2 long-term (more than 12 months) [60]. Of note, both activated (FOXP3high CD45RAlow) and cytokine-producing non-Treg (FOXP3low CD45RAlow) were expanded in that context, suggesting a double activity of IFN in promoting both effector and regulatory responses [60]. Conversely, another study has analyzed Treg frequency, as CD4+ FOXP3+ CD25high cells, in the peripheral blood of melanoma patients at very early time points (from 8 to 29 days) during IFN-a2b therapy, and found a gradual decrease in Treg percentage in most of the patients, reaching statistical significance at 4 weeks [61].…”

“…In a neo-adjuvant regimen of high-dose IFN-a2b administration to melanoma patients, the percentage of FOXP3+ cells in lymphocytes was increased, in association to STAT5 upregulation, as evaluated by immunohistochemistry in biopsy specimens of regional lymph nodes, 29 days after therapy compared to pre-treatment [59]. Another study has confirmed the increase of Treg, enumerated in the peripheral blood by flow cytometry as CD4+ FOXP3+ CD25high cells, in patients with chronic myeloproliferative disorders, treated with peg-IFN-a2 long-term (more than 12 months) [60]. Of note, both activated (FOXP3high CD45RAlow) and cytokine-producing non-Treg (FOXP3low CD45RAlow) were expanded in that context, suggesting a double activity of IFN in promoting both effector and regulatory responses [60].…”

Reduced frequency of circulating CD4+CD25brightCD127lowFOXP3+ regulatory T cells in primary myelofibrosis

“…16 There are contradictory data on numbers of Tregs in persons with PMF. [17][18][19] With the aim of determining whether Tregs were abnormal and interrogating possible associations with clinical and laboratory features, we did a cross-sectional evaluation of 202 consecutive subjects with PMF referred to the Center for the Study of Myelofibrosis, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo of Pavia, Italy, from March 2008 to September 2015 (supplemental Methods, available on the Blood Web site). Sample size was defined by investigating blood Treg frequency in 31 subjects with PMF tested twice within 5 days.…”