IFN-λ Cancer Immunotherapy: New Kid on the Block

Abstract

Interferon-lambda (IFN-λ) is a new IFN type, related to IFN-α, that is commonly used in the clinic. However, significant side effects accompanying IFN-α treatment limit enthusiasm for IFN-α. In this review, we discuss the current landscape of IFN-α use in oncology and describe the biologic characteristics of IFN-λ. IFN-λ offers unique advantages, including a more tumor cell selective targeting, lower off-target binding and an ability to generate both innate and adaptive immune responses. IFN-λ has also demonstrated therapeutic benefit in murine cancer models. IFN-λ may be used in clinic as a single agent or in combination with other immunotherapy agents, such as immune checkpoint inhibitors. Further clinical trials will be needed to fully elucidate the potential of this novel agent in oncology.

Interferon-λs and Plasmacytoid Dendritic Cells: A Close Relationship

“…However, if properly stimulated, pDCs can also promote antitumoral response, for instance, by directly killing tumor cells through TRAIL expression ( 75 ), or indirectly via IFNα, which mediates NK cell activation. Thus, based on our unpublished observations indicating that IFNλs, in addition to triggering IFNα production, also induce TRAIL mRNA expression in human pDCs, it would be plausible speculating a potential use of IFNλs as adjuvants to chemotherapy regimens ( 76 ). Accordingly, IFNλs may induce antitumor activities either by directly acting on tumor cells and intratumor pDCs, or by indirectly favoring the recruitment and activation of immune cells, to ultimately kill tumor cells (Figure 1 ).…”

Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma

“…Relevantly, III-IFNs exert direct effects on cancer cells by inhibiting cell proliferation and promoting apoptosis. In addition, III-IFNs have indirect effects against multiple tumors by inducing T cells and NK cells response [84][85][86]. pDCs produce IFN-λ1/3 in response to either stimulation by viruses or synthetic TLR9 agonists, independently of IFN-α [87,88].…”

IFN-λ: A New Inducer of Local Immunity against Cancer and Infections

“…NK cells are well armed for sensing and killing virus-infected cells (Figure 2). In vivo activation of NK cells by IFN-λ has been well documented in cancer models (6, 65). Significant NK cell impairment of NK cell tumoricidal activity has been reported in IFN-λR−/− mice (66).…”

“…However, we did not find yet a corresponding IFN-λ4 in mice. Type III IFNs use a unique receptor, the IFN-λ receptor, and induces similar JAK–STAT signaling pathway as type I IFNs (5, 6). Although it has been well established that in addition to JAK1, TYK2 is crucial in mediating the activity of both type I and type III IFN, new evidence in patients with a defect in TYK2 shows an impaired response for type I IFN only (7), suggesting a Tyk2-independent signaling for type III IFN.…”

“…Type I IFN interacts with a receptor formed by IFNAR1 and IFNAR2 (8). However, type III IFNs bind to the specific receptor chain IFN-λR1, and IL-10R2, a receptor subunit shared by IL-10 cytokine family members IL-10, IL-22, and IL-26 (6). In contrast to type I and type II IFN receptors, the unique type III IFN receptor for IFN-λ, IFN-λR1 is not ubiquitously expressed (5, 9), suggesting that IFN-λ may eradicate specific viral infections and also elicit a more local immunity against pathogens and cancers.…”