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Targeting AKT signaling sensitizes cancer to cellular immunotherapy

Patricia S Hähnel1, Sonja Thaler, Edite Antunes

  • 1Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, Essen, Germany.

Cancer Research
|May 17, 2008
PubMed

Insights

Cancer cells with activated Protein Kinase B (PKB)/AKT signaling resist immune attack. Inhibiting this pathway, particularly with mTOR inhibitors like rapamycin, can restore sensitivity to cancer immunotherapy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Cancer immunotherapy offers targeted treatment but faces challenges due to tumor escape mechanisms.
  • Deregulated growth and survival signaling pathways are common in cancers and may contribute to immune evasion.

Purpose of the Study:

  • To investigate if activated cell-autonomous signaling pathways, specifically Protein Kinase B (PKB)/AKT, confer resistance to anti-cancer immune responses.
  • To explore the role of Mcl-1 and the mammalian target of rapamycin (mTOR) pathway in PKB/AKT-mediated immune resistance.

Main Methods:

  • Utilized two cancer models to assess tumor resistance to cytotoxic T lymphocytes (CTLs) and adoptive immunotherapy.
  • Employed genetic suppression of Mcl-1 and treatment with the mTOR inhibitor rapamycin.
  • Analyzed the impact of PKB/AKT signaling on Mcl-1 expression and tumor cell susceptibility to immune attack.

Main Results:

  • Activated PKB/AKT signaling confers resistance to both in vitro CTL-mediated killing and in vivo adoptive immunotherapy.
  • Suppression of Mcl-1, an anti-apoptotic protein, reversed PKB/AKT-mediated immune resistance.
  • mTOR-dependent stabilization of Mcl-1 by PKB/AKT was identified as a key mechanism of immune evasion.
  • Rapamycin treatment sensitized established tumors to adoptive immunotherapy.

Conclusions:

  • Cancer cell-intrinsic PKB/AKT signaling is a critical determinant of susceptibility to immune-mediated cytotoxicity.
  • Targeting signal transduction pathways, such as PKB/AKT and mTOR, alongside immunotherapy holds promise for improving treatment efficacy.

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