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Review
. 2013 Apr;33(4):171-80.
doi: 10.1089/jir.2012.0087.

Interferon-γ-induced necrosis: an antitumor biotherapeutic perspective

Siddharth Balachandran  1 , Gregory P Adams
Affiliations
Review

Interferon-γ-induced necrosis: an antitumor biotherapeutic perspective

Siddharth Balachandran et al. J Interferon Cytokine Res. 2013 Apr.

Abstract

Interferon (IFN)-γ-like the well-known antitumor biotherapeutic IFN-α-is a powerful antiproliferative and immune modulatory cytokine, but mixed results from clinical trials, together with issues of systemic toxicity, have dampened enthusiasm for its use in the treatment of cancer. We suggest that at least 2 factors reduce the antitumor efficacy of IFN-γ: (1) poorly understood survival mechanisms that protect most tumor cells from IFN-γ-induced direct cytotoxicity, and (2) the short half-life of IFN-γ in serum. In this review, we outline avenues to overcome both these limitations. First, we have identified the transcription factor nuclear factor-kappa B (NF-κB) as a protective mechanism against IFN-γ-induced necrosis, and disabling NF-κB allows IFN-γ to trigger RIP1 kinase-dependent programmed necrosis (or necroptosis) in otherwise resistant cells. Second, we propose that fusing IFN-γ to tumor-specific antibodies will stabilize IFN-γ in serum and target this cytokine to tumor cells. We expect that such IFN-γ-antibody chimeras (called immunocytokines), when combined with agents that neutralize tumor-intrinsic survival signals such as NF-κB, will exert potent tumoricidal activity with minimized systemic side effects. Although this review will focus on exploiting IFN-γ-induced necrosis for treatment of renal cell carcinoma, these approaches are also directly applicable to several human cancers in which IFNs have shown therapeutic potential.

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Figures

FIG. 1.
FIG. 1.
Schematic of interferon (IFN)-γ-activated pronecrotic and prosurvival signaling pathways. IFN-γ utilizes classical Jak/STAT signaling downstream of the IFN-γ receptor (IFNGR) to induce expression of pronecrotic genes (such as those encoding RIP1, PKR, and MLKL proteins) and activate R1P1/RIP3 kinase-dependent necrosis. The IFN-γ-induced necrotic pathway is held in check by the adaptor protein FADD, and can be inhibited by the RIP1 kinase blocker Necrostatin-1. In parallel, IFN-γ also activates NF-κB via canonical IκB kinases (IKK)-β-dependent signaling to induce expression of prosurvival genes such as sod2. As NF-κB target genes protect against IFN-γ-activated necrosis, disabling NF-κB signaling (by bortezomib, for example) sensitizes cells to IFN-γ-induced necrotic death that proceeds via accumulation of mitochondrial reactive oxygen species (ROS).
FIG. 2.
FIG. 2.
Schematic of IFN-γ fusion immunocytokine. IFN-γ is fused to the carboxyl terminus of the heavy chain of a tumor-targeting antibody with a flexible, protease-resistant linker. Fusion to an antibody not only targets IFN-γ to tumor cells, but also improves its stability in serum.
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