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T cells expressing constitutively active Akt resist multiple tumor-associated inhibitory mechanisms

Jiali Sun1, Gianpietro Dotti, Leslie E Huye

  • 1Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|September 16, 2010
PubMed

Insights

Constitutively active Akt (caAkt) enhances T-cell function and survival, making them resistant to tumor-induced suppression. This modification improves T-cell therapy for cancer by overcoming tumor evasion strategies.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Adoptive T-cell therapy shows promise for cancer treatment.
  • Tumor microenvironments often inhibit T-cell function.
  • The Akt/protein kinase B pathway is crucial for T-cell responses.

Purpose of the Study:

  • To investigate if constitutively active Akt (caAkt) expression in T cells enhances resistance to tumor-associated inhibitory mechanisms.
  • To evaluate the impact of caAkt on T-cell proliferation, survival, and function in the context of cancer immunotherapy.

Main Methods:

  • Human T cells were engineered to express caAkt.
  • T-cell proliferation, cytokine production, and apoptosis resistance were assessed.
  • T cells were co-cultured with neuroblastoma cells (LAN-1) expressing GD2.
  • Chimeric antigen receptor (CAR) T cells targeting GD2 were engineered with caAkt.

Main Results:

  • caAkt expression increased T-cell proliferation and cytokine production, linked to sustained nuclear factor-κB (NF-κB) activity.
  • caAkt-expressing T cells exhibited resistance to apoptosis via upregulation of antiapoptotic molecules.
  • caAkt-T cells showed reduced susceptibility to suppression and conversion into regulatory T cells (Tregs).
  • CAR T cells co-expressing caAkt demonstrated enhanced survival when co-cultured with GD2-positive neuroblastoma cells in vitro.

Conclusions:

  • caAkt-transduced T cells overcome several tumor evasion strategies.
  • Enhanced T-cell resistance to tumor-induced inhibition may improve the efficacy of adoptive T-cell immunotherapy for cancer.

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