Modulation of Signal Transducers and Activators of Transcription 1 and 3 Signaling in Melanoma by High-Dose IFNα2b

Abstract

Purpose: The Janus-activated kinase/signal transducers and activators of transcription (STAT) pathway of IFN signaling is important to immunoregulation and tumor progression. STAT1plays a prominent role in the effector immune response, whereas STAT3 is implicated in tumor progression and down-regulation of the response to type IIFNs.The goal of this study was to understand the effects of high-dose IFNa2b (HDI) in relation to the balance of pSTAT1and pSTAT3. Experimental Design: We evaluated STAT1 and STAT3 jointly as mediators of IFNa effects in the setting of a prospective neoadjuvant trial of HDI, in which tissue samples were obtained before and after 20 doses of HDI therapy. Double immunohistochemistry for pSTAT1and pSTAT3 was done on paired fixed (9 patients) or frozen (12 patients) biopsies. Results: HDI was found to up-regulate pSTAT1, whereas it down-regulates pSTAT3 and total STAT3 levels in both tumor cells and lymphocytes. Higher pSTAT1/pSTAT3 ratios in tumor cells pretreatment were associated with longer overall survival (P = 0.032). The pSTAT1/pSTAT3 ratios were augmented by HDI both in melanoma cells (P = 0.005) and in lymphocytes (P = 0.022). Of the immunologic mediators and markers tested,TAP2 was augmented by HDI (but not TAP1and MHC class I/II). Conclusion: IFNa2b significantly modulates the balance of STAT1/STAT3 in tumor cells and host lymphocytes, leading to up-regulation of TAP2 and augmented host antitumor response. The pSTAT1/pSTAT3 ratio in tumor cells at baseline may serve as a useful predictor of clinical outcome in cutaneous melanoma; the modulation of this ratio may serve as a predictor of therapeutic effect.High-dose IFNa2b (HDI) is the only therapy that has shown a reproducible ability to prolong both relapse-free and overall survival of patients with resected high-risk, deep, primary, or lymph node metastatic melanoma. This therapy has consistently shown a capacity to reduce the hazard of relapse and mortality by 22% to 33% in multiple U.S. intergroup studies done over the past 20 years (1 -3). However, in the past decade, no further progress in the adjuvant therapy of melanoma has occurred, and the gap in our knowledge of the IFNa2b mechanism has proven to be a major impediment to further progress. A better understanding of the mechanism(s) of HDI in the adjuvant therapy of melanoma would enable more effective application of this therapy, and more intelligent strategies building upon this modality.The antitumor effects of IFNa2b include direct inhibition of tumor cell growth and the modulation of host immune response to tumor. The Janus-activated kinase/signal transducers and activators of transcription (STAT) signal pathway is one of the major mechanisms of IFNa2b action. Both human type I IFNa receptor chains 1 and 2 are required for the type I IFN -dependent signaling pathways. The intracellular domains of these receptors are associated with Janus-activated kinases, which are activated upon IFNa2b binding to its receptors. Janus-activated kinases then phosphorylate ...

Role of Stat3 in suppressing anti-tumor immunity

“…As evidence accumulating in mouse models that inhibiting Stat3 can boost the efficacies of immunotherapy, supporting data from clinical trials are also emerging. A recent study of prospective neoadjuvant trial of interferon-α therapy suggests that higher phosphorylated Stat1 (pStat1) over phosphorylated Stat3 in both tumor cells and lymphocytes pretreatment were associated with longer overall survival [49]. In addition, high density interferon-α treatment is associated with upregulation of pStat1 and down-regulation of pStat3 [49].…”

“…A recent study of prospective neoadjuvant trial of interferon-α therapy suggests that higher phosphorylated Stat1 (pStat1) over phosphorylated Stat3 in both tumor cells and lymphocytes pretreatment were associated with longer overall survival [49]. In addition, high density interferon-α treatment is associated with upregulation of pStat1 and down-regulation of pStat3 [49]. These data suggest that the ratio between pStat1/pStat3 at the baseline could serve as a predictor of clinical outcome of certain immunotherapies and that increasing this ratio may tip the balance towards better immunotherapeutic effects.…”

Dynamic Balance of pSTAT1 and pSTAT3 in C57BL/6 Mice Infected with Lethal Or Nonlethal Plasmodium yoelii

“…In contrast, the lethal Py17XL infection induced a pSTAT3-dominant response during the whole short course with the death of the animals. The pSTAT1/pSTAT3 ratio has been evaluated as an important index for immunoregulation (26,31,35,36), so we analyzed the constituent ratio of pSTAT1 and pSTAT3 in the spleen during the whole course of Py17XNL ( Figure 2G) or Py17XL ( Figure 2H) infection. The pSTAT1/pSTAT3 ratio was increased during the early stage of Py17XNL infection, peaked on day 7 p.i., and subsequently decreased.…”

“…So the balance of pSTAT1 and pSTAT3, which has been studied in cancer immunity (31,34), has an important role in regulation of immune responses. A higher pSTAT1/pSTAT3 ratio in tumor cell or in immune cell is associated with longer survival for tumor patients (26,31,35,36). However, this balance has not been studied in malaria immunology.…”

Enhancing efficacy of therapeutic vaccinations by combination with other modalities

“…In addition, antigen presentation to CD8 + CTL usually involves proteolytic cleavage of antigen in the cytosol and delivery of epitope peptides onto MHC class I molecules in the endoplasmic reticulum via the heterodimeric peptide transporter TAP1/TAP2. In a recent study, Wang et al demonstrated that IFN-alpha2b significantly modulates the balance of STAT1/STAT3 in tumor cells and host lymphocytes, leading to up-regulation of TAP2 and augmented host antitumor response [22]. Chemotherapy agents commonly used in cancer therapy, such as 5-fluorouracil, have also been shown to up-regulate CEA and MHC class I in tumor cells.…”