Anti-metastatic functions of type 1 interferons: Foundation for the adjuvant therapy of cancer

Abstract

The anti-tumorigenic effects that type 1 interferons (IFN1) elicited in the in vitro studies prompted consideration of IFN1 as a potent candidate for clinical treatment. Though not all patients responded to IFN1, clinical trials have shown that patients with high risk melanoma, a highly refractory solid malignancy, benefit greatly from intermediate IFN1 treatment in regards to relapse-free and distant-metastasis-free survival. The mechanisms by which IFN1 treatment at early stages of disease suppress tumor recurrence or metastatic incidence are not fully understood. Intracellular IFN1 signaling is known to affect cell differentiation, proliferation, and apoptosis. Moreover, recent studies have revealed specific IFN1-regulated genes that may contribute to IFN1-mediated suppression of cancer progression and metastasis. In concert, expression of these different IFN1 stimulated genes may impede numerous mechanisms that mediate metastatic process. Though, IFN1 treatment is still utilized as part of standard care for metastatic melanoma (alone or in combination with other therapies), cancers find the ways to develop insensitivity to IFN1 treatment allowing for unconstrained disease progression. To determine how and when IFN1 treatment would be most efficacious during disease progression, we must understand how IFN1 signaling affects different metastasis steps. Here, we specifically focus on the anti-metastatic role of endogenous IFN1 and parameters that may help to use pharmaceutical IFN1 in the adjuvant treatment to prevent cancer recurrence and metastatic disease.

Serum proteomic analysis of melanoma patients with immunohistochemical profiling of primary melanomas and cultured cells: Pilot study

“…The low levels of IFNα in patients with melanoma seem to be important, because its anticancer effect has been well documented and recombinant IFNα is employed as a drug in cancer therapy, including adjuvant therapy for MM (36). Similar therapeutic implications are true for IL-2 (37).…”

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

“…Type I interferons exhibit various anti-metastatic functions including upregulation of E-cadherin, suppression of angiogenesis and interference with metastatic cancer cell homing. 27,28 As plasmacytoid DCs (pDCs) are the major cellular source of IFN alpha in humans, 29 we speculated that pDC infiltration and associated intrinsic IFN signalling could be altered in ulcerated melanoma, which would possibly explain the exclusive sensitivity of patients with ulcerated primaries to adjuvant IFN alpha. 10 However, tumour infiltration with pDCs did not differ between ulcerated and non-ulcerated primary tumours, neither did tumour cell expression of the IFN alpha-induced protein MxA.…”

The PKR-Like Endoplasmic Reticulum Kinase Promotes the Dissemination of Myc-Induced Leukemic Cells

“…The mechanisms by which PERK expression in the cells harboring activated Myc supports the dissemination of these cells remain to be elucidated. One of potential mechanisms we considered is the alteration of IFN signaling, which is known to suppress the metastatic processes and contribute to expression of numerous chemokines and their receptors that could guide leukemic cells' dissemination (44,45). Indeed, previous reports suggested that PERK signals toward accelerated ubiquitination and degradation of the IFNAR1 chain of IFN receptor (9).…”