Interferon-alpha in tumor immunity and immunotherapy

Belardelli, Filippo; Ferrantini, Maria; Proietti, Enrico; Kirkwood, John M.

doi:10.1016/s1359-6101(01)00022-3

Cited by 314 publications

(217 citation statements)

References 92 publications

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“…Despite 45 years since the discovery of IFN (Pfeffer et al, 1998) and two decades since the first IFN treatment experience in mRCC (Quesada et al, 1983), the exact mechanisms underlying the antitumour response are not fully understood (Belardelli et al, 2002). Our tumour tissue analyses demonstrated only modest reduction in the number of proliferating tumour cells induced by IFN-a and IL-2, suggesting that immunotherapy reduces tumour size but has only limited effect on intrinsic tumour aggressiveness in vivo.…”

Section: Discussionmentioning

confidence: 99%

In vivo assessment of the antiproliferative properties of interferon-alpha during immunotherapy: Ki-67 (MIB-1) in patients with metastatic renal cell carcinoma

et al. 2004

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The aim of the present study was to investigate the in vivo antiproliferative effect of interferon alpha (IFN-a) in patients with metastatic renal cell carcinoma (mRCC). Core needle biopsies of metastatic and/or the primary kidney cancer were obtained before interleukin-2 (IL-2)-and IFN-a-based immunotherapy in 34 patients and repeated after 5 weeks in 25 patients. Tumour proliferation was assessed by use of the anti-Ki-67 antibody MIB-1 and evaluated in multiple, random systematic sampled fields of vision. Ki-67 labelling index (LI) at baseline was median 13.6% (range 1.2 -85.0) and median 10.6% (range 1.3 -48.6%) at week 5 with a median overall decline of 15.2% (range À95 to þ 258%) from baseline to week 5. There was no difference between responding and nonresponding patients. Ki-67 LI at week 5 was significantly correlated to survival. Thus, median survival of patients with Ki-67 LI p10.6% at week 5 was 25.1 months compared to 11.5 months for patients with Ki-67 LI 410.6% (P ¼ 0.016). Baseline or change in Ki-67 LI did not correlate to survival. These data suggest that IFN-a in vivo has only modest effect on tumour proliferation in patients with mRCC. Tumour Ki-67 (MIB-1) reactivity after 1 month of immunotherapy appears to be a significant predictor of patient survival.

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Section: Discussionmentioning

confidence: 99%

In vivo assessment of the antiproliferative properties of interferon-alpha during immunotherapy: Ki-67 (MIB-1) in patients with metastatic renal cell carcinoma

et al. 2004

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“…Type I IFNs (IFN-a/h) have shown significant antitumor activity in animal models (1-3) through a variety of mechanisms, including direct tumor cell cytotoxicity (4), immunomodulation (5), and inhibition of angiogenesis (6)(7)(8)(9). However, despite promising preclinical results, the antitumor efficacy of type I IFNs in treating human cancer has been disappointing (10).…”

Section: Introductionmentioning

confidence: 99%

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

Dickson¹,

Hamner²,

Streck³

et al. 2007

Molecular Cancer Research

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IFNs have pleiotropic antitumor mechanisms of action. The purpose of this study was to further investigate the effects of IFN-B on the vasculature of human xenografts in immunodeficient mice. We found that continuous, systemic IFN-B delivery, established with liver-targeted adeno-associated virus vectors, led to sustained morphologic and functional changes of the tumor vasculature that were consistent with vessel maturation. These changes included increased smooth muscle cell coverage of tumor vessels, improved intratumoral blood flow, and decreased vessel permeability, tumor interstitial pressure, and intratumoral hypoxia. Although these changes in the tumor vasculature resulted in more efficient tumor perfusion, further tumor growth was restricted, as the mature vasculature seemed to be unable to expand to support further tumor growth. In addition, maturation of the intratumoral vasculature resulted in increased intratumoral penetration of systemically administered chemotherapy. Finally, molecular analysis revealed increased expression by treated tumors of angiopoietin-1, a cytokine known to promote vessel stabilization. Induction of angiopoietin-1 expression in response to IFN-B was broadly observed in different tumor lines but not in those with defects in IFN signaling. In addition, IFN-B -mediated vascular changes were prevented when angiopoietin signaling was blocked with a decoy receptor. Thus, we have identified an alternative approach for achieving sustained vascular remodeling-continuous delivery of IFN-B. In addition to restricting tumor growth by inhibiting further angiogenesis, maturation of the tumor vasculature also improved the efficiency of delivery of adjuvant therapy. These results have significant implications for the planning of combination anticancer therapy.

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“…1 IFNs are also important negative growth factors that inhibit cell proliferation and induce apoptosis. 2 Three major classes of IFNs, including IFN-a, IFN-b, and IFN-g, have been identified. 3 Retinoic acids (RAs) are natural and synthetic derivatives of Vitamin A. Alltrans-retinoic acid and 9-cis-RA are active metabolites that bind and activate the nuclear receptors, all-trans-RA receptors (RARs) and retinoid X receptors (RXRs), and control expression of various genes.…”

mentioning

confidence: 99%

Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-β and retinoic acid-induced cancer cell death

Huang

Chen

et al. 2006

Cell Death Differ

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Combination of retinoic acids (RAs) and interferons (IFNs) has synergistic apoptotic effects and is used in cancer treatment. However, the underlying mechanisms remain unknown. Here, we demonstrate that mitochondrial respiratory chain (MRC) plays an essential role in the IFN-b/RA-induced cancer cell death. We found that IFN-b/RA upregulates the expression of MRC complex subunits. Mitochondrial-nuclear translocation of these subunits was not observed, but overproduction of reactive oxygen species (ROS), which causes loss of mitochondrial function, was detected upon IFN-b/RA treatment. Knockdown of GRIM-19 (gene associated with retinoid-interferon-induced mortality-19) and NDUFS3 (NADH dehydrogenase (ubiquinone) Fe-S protein 3), two subunits of MRC complex I, by siRNA in two cancer cell lines conferred resistance to IFN-b/RA-induced apoptosis and reduced ROS production. In parallel, expression of late genes induced by IFN-b/RA that are directly involved in growth inhibition and cell death was also repressed in the knockdown cells. Our data suggest that the MRC regulates IFN-b/RA-induced cell death by modulating ROS production and late gene expression.

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Interferon-alpha in tumor immunity and immunotherapy

Cited by 314 publications

References 92 publications

In vivo assessment of the antiproliferative properties of interferon-alpha during immunotherapy: Ki-67 (MIB-1) in patients with metastatic renal cell carcinoma

In vivo assessment of the antiproliferative properties of interferon-alpha during immunotherapy: Ki-67 (MIB-1) in patients with metastatic renal cell carcinoma

Continuous Delivery of IFN-β Promotes Sustained Maturation of Intratumoral Vasculature

Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-β and retinoic acid-induced cancer cell death

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