Antitumor activity of type III interferon alone or in combination with type I interferon against human non-small cell lung cancer

Our plain-English summary of Antitumor activity of type III interferon alone or in combination with type I interferon against human non-small cell lung cancer, by H. Fujie, T. Tanaka, M. Tagawa, et al (Cancer Science, 2011).

The study

• Authors: H. Fujie, T. Tanaka, M. Tagawa, N. Kaijun, M. Watanabe, T. Suzuki, K. Nakayama, M. Numasaki
• Journal: Cancer Science
• Published: 2011;102(11):1977-90
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The antitumor activities of type III interferon (IFN) (interleukin [IL]-28 and IL-29) and the combination of type III IFN and type I IFN (IFN-α) were evaluated using human non-small cell lung cancer (NSCLC). The expression of type III and type I receptor complexes was detected in NSCLC lines. IL-29 significantly inhibited the in vitro growth of a wide range of NSCLC lines in a dose-dependent fashion. To a lesser degree, IL-28A also displayed growth inhibitory activity. Antitumor activity of type III IFN is associated with cell cycle arrest at the G1 phase and apoptosis. IL-29 upregulated cyclin-dependent kinase inhibitor p21Waf1/Cip1 in cells sensitive, but not insensitive, to antiproliferative activity, and knockdown of p21 with small interfering RNA largely attenuated the antiproliferative effect. Intratumoral and systemic administration of IL-29 inhibited OBA-LK1 and LK-1, but not A549, tumor growth in severe combined immunodeficiency mice. Immunohistochemical analyses demonstrated marked upregulated p21 and downregulated Ki-67 expression in tumors treated with IL-29. The interferon combination of IL-29 and IFN-α displayed a more effective antiproliferative effect and a more intense p21 expression than each reagent alone in vitro. Furthermore, interferon combination therapy suppressed in vivo NSCLC growth more effectively than interferon monotherapy. These findings demonstrate that type III IFN can mediate direct antitumor activities via increased p21 expression and induction of apoptosis and cooperate with type I IFN to elicit more efficient direct antitumor activities, and suggest the possibility that type III IFN might improve the efficacy and reduce the side-effects of type I IFN cancer therapy.

© 2011 Japanese Cancer Association.

In plain English

This laboratory study did not examine asbestos exposure. The authors tested whether type III interferons (IL-28A and IL-29), alone or combined with the type I interferon IFN-alpha, slowed the growth of human non-small cell lung cancer. They used 12 lung cancer cell lines and grew tumors from three of them in immune-deficient mice. One malignant mesothelioma cell line, H28, was included only in receptor tests, and the type III receptor IL-28R was not detected in it. IL-29 slowed growth of a wide range of the lung cancer lines in a dose-dependent way, and IL-28A did so to a lesser extent. Three lines were sensitive, three intermediate and six insensitive. In sensitive lines, IL-29 stopped cells at the G1 stage of division, raised levels of the protein p21 and triggered cell death. In mice, IL-29 reduced the volume of OBA-LK1 and LK-1 tumors compared with control mice, but not significantly for A549 tumors. Combining IL-29 with IFN-alpha worked better than either alone. The authors concluded that type III interferon has direct antitumor activity against this cancer.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study using human cancer cell lines (in vitro) and tumors grown from those cells in mice (animal experiment)
• Who was studied: 12 human non-small cell lung cancer cell lines and one malignant mesothelioma cell line (H28). Tumors from three lung cancer lines (OBA-LK1, LK-1, A549) were grown in severe combined immunodeficiency (SCID) mice, with five mice per group for injection into the tumor and four per group for systemic treatment.
• Exposure: No asbestos exposure was studied. The treatments were type III interferons (IL-28A, IL-29) and type I interferon (IFN-alpha), alone or in combination, compared with PBS (saline) controls in mice.
• Main results:
  • In the malignant mesothelioma line H28, the transcript for the type III interferon receptor IL-28R was not detected. It was found in all 12 lung cancer lines.
  • IL-29 inhibited the growth of a wide range of the lung cancer cell lines in a dose-dependent way. IL-28A had a weaker effect on a more limited range of lines.
  • Three lines (11–18, OBA-LK1, 86-2) were sensitive to type III interferon. Six were insensitive (Lu99, NCI-H23, EBC-1, LK-2, Sq-19, A549) and three were intermediate (Sq-1, LK-79, LK-1).
  • In the sensitive OBA-LK1 line, 50 or 250 ng/mL IL-29 raised the share of cells in the G1 phase from 53% to 69% or 80%. In the 11–18 line the share rose from 30% to 61% or 79%. There was no change in the insensitive A549 line.
  • IL-29 increased p21 protein in the sensitive lines OBA-LK1 and 11–18 but not in A549. Blocking p21 with siRNA significantly reduced IL-29's growth-inhibiting effect in OBA-LK1 cells.
  • In mice, after three weeks of IL-29 injected into the tumor at 0.05, 0.4 or 1.5 micrograms, OBA-LK1 tumor volume was 30%, 66% or 69% lower than in controls.
  • With the same intratumoral doses, LK-1 tumor volume was 22%, 35% or 50% lower than in controls.
  • Systemic IL-29 at 0.4, 1.5 or 7 micrograms per mouse per day reduced OBA-LK1 tumor volume by 20%, 47% or 65% compared with controls. Tumors did not regress or disappear.
  • In A549 tumors, which were insensitive in the dish, daily intratumoral IL-29 (400 ng) did not significantly suppress growth compared with PBS (P = 0.1936).
  • With 7 micrograms daily systemic IL-29, 27.8% of tumor cells stained positive for p21, compared with 18.3% in PBS-treated tumors (P less than 0.03). IL-29 did not affect tumor blood vessel density.
  • Type III interferon treatment did not appear to cause significant adverse reactions in the mice.
  • In OBA-LK1 tumors in mice, IL-29, IFN-alpha and their combination all slowed tumor growth. The combination had the greatest effect.
• The authors' conclusion: The authors concluded that type III interferon can act directly against non-small cell lung cancer in cell cultures and in mice, mainly through increased p21 and induction of apoptosis (cell death), and that it can cooperate with type I interferon to do so more efficiently.
• Limitations the authors state:
  • The authors stated they have no evidence that the interferon combination works additively or synergistically against other types of human tumors.
  • Blocking p21 did not completely abolish IL-29's growth inhibition. The authors said further analyses are required.
  • The authors stated that the mechanisms by which the interferon combination worked better than either agent alone remain to be clarified.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Non-Small Cell Lung Cancer, Apoptosis, Ki-67.

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