Interferon Alpha Signalling and Its Relevance for the Upregulatory Effect of Transporter Proteins Associated with Antigen Processing (TAP) in Patients with Malignant Melanoma

Abstract

IntroductionInterferon alpha (IFNα) is routinely used in the clinical practice for adjuvant systemic melanoma therapy. Understanding the molecular mechanism of IFNα effects and prediction of response in the IFNα therapy regime allows initiation and continuation of IFNα treatment for responder and exclusion of non-responder to avoid therapy inefficacy and side-effects. The transporter protein associated with antigen processing-1 (TAP1) is part of the MHC class I peptide-loading complex, and important for antigen presentation in tumor and antigen presenting cells. In the context of personalized medicine, we address this potential biomarker TAP1 as a target of IFNα signalling.ResultsWe could show that IFNα upregulates TAP1 expression in peripheral blood mononuclear cells (PBMCs) of patients with malignant melanoma receiving adjuvant high-dose immunotherapy. IFNα also induced expression of TAP1 in mouse blood and tumor tissue and suppressed the formation of melanoma metastasis in an in vivo B16 tumor model. Besides its expression, TAP binding affinity and transport activity is induced by IFNα in human monocytic THP1 cells. Furthermore, our data revealed that IFNα clearly activates phosphorylation of STAT1 and STAT3 in THP1 and A375 melanoma cells. Inhibition of Janus kinases abrogates the IFNα-induced TAP1 expression. These results suggest that the JAK/STAT pathway is a crucial mediator for TAP1 expression elicited by IFNα treatment.ConclusionWe suppose that silencing of TAP1 expression provides tumor cells with a mechanism to escape cytotoxic T-lymphocyte recognition. The observed benefit of IFNα treatment could be mediated by the shown dual effect of TAP1 upregulation in antigen presenting cells on the one hand, and of TAP1 upregulation in ‘silent’ metastatic melanoma cells on the other hand. In conclusion, this work contributes to a better understanding of the mode of action of IFNα which is essential to identify markers to predict, assess and monitor therapeutic response of IFNα treatment in the future.

Increased tumour cell PD‐L1 expression, macrophage and dendritic cell infiltration characterise the tumour microenvironment of ulcerated primary melanomas

“…30 IFN alpha has been reported to upregulate TAP1 expression in peripheral blood mononuclear cells of treated patients as well as in murine blood and tumour tissue in this context. 31 Despite these previous findings, our data on TAP1 Figure 2 Immunohistochemistry representative of differences between ulcerated and non-ulcerated tumours (2009 magnification). Both CD163 + macrophages (a) and CD11 + dendritic cells (b) were more frequently detected in high numbers in ulcerated (right-sided images) than in non-ulcerated tumours (left-sided images).…”

TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer

“…Interferons (both a and gamma) are expressed by activated T-lymphocytes and have been shown to upregulate the expression of various components of the antigen presenting machinery, including TAP1. [23][24][25] In this study, tumors with intact TAP1 expression were more infiltrated by immune cells posing the question of whether TAP1 expression may be supported by interferons secreted by the infiltrating immune cells? Then it would rather be that immune infiltration would support an intact APM, thus conserving the immunogenicity of the tumor, than vice versa.…”

“…Interferons have shown promising therapeutic effects in melanoma patients, 26 and a link has been suggested to an upregulation of APM-molecules. 23 Identifying patients with tumors lacking TAP1 expression could therefore be of relevance in the future of personalized therapy.…”

Cell Signaling Pathways That Regulate Antigen Presentation

“…In each of these cases, it is likely that a virus-encoded protein(s) prevented IFN-γ-induced activation of the JAK/STAT pathway. Similarly, immune evasion by solid tumors can be due to an impairment of JAK/STAT signaling that prevents the upregulation of MHC class I molecules (12, 14) or TAP1 expression (9). …”