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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
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Published on: January 7, 2019

Adenovirus CD40 ligand gene therapy counteracts immune escape mechanisms in the tumor Microenvironment

Angelica Loskog1, Helena Dzojic, Sofia Vikman

  • 1Clinical Immunology Division, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden. aloskog@bcm.tmc.edu

Journal of Immunology (Baltimore, Md. : 1950)
|May 22, 2004
PubMed

Insights

Adenovirus CD40 ligand (CD40L) gene transfer combats tumor immune evasion by suppressing immunosuppressive factors and promoting Th1 immune responses. This immunotherapy effectively regressed tumors and inhibited progression in a murine model, offering a promising cancer treatment strategy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Gene Therapy

Background:

  • Tumors utilize immune escape mechanisms like immunosuppression and resistance to apoptosis, hindering immunotherapies.
  • Interleukin-10 (IL-10) secreted by tumors inhibits dendritic cell maturation and cytotoxic T lymphocyte (CTL) activation.
  • Th2-type immune responses are often associated with tumor immune evasion.

Purpose of the Study:

  • To investigate the immunological effects of introducing CD40 ligand (CD40L) into the tumor microenvironment via adenoviral gene transfer.
  • To assess the potential of CD40L immunogene therapy to overcome tumor-induced immunosuppression in a murine bladder cancer model.

Main Methods:

  • Adenoviral gene transfer of CD40 ligand (CD40L) into a murine bladder cancer model (MB49).
  • Analysis of cytokine production (IL-10, TGF-beta, IL-12) in the tumor area.
  • Assessment of CD8(+) T cell cytotoxicity and dendritic cell maturation.
  • Evaluation of tumor regression and progression in treated mice.

Main Results:

  • CD40L immunogene therapy significantly suppressed IL-10 and TGF-beta production (2-fold decrease).
  • A substantial increase in IL-12 production (200-fold) indicated a shift towards a Th1-type immune response.
  • Adenovirus CD40L therapy led to the regression of small tumors and inhibited the progression of larger tumors.
  • CD40L-transduced cells promoted dendritic cell maturation independently of IL-10.

Conclusions:

  • Adenovirus-mediated CD40L gene transfer is effective in reversing tumor-induced immunosuppression and promoting anti-tumor immunity.
  • CD40L therapy can overcome immune escape mechanisms, including apoptosis resistance and IL-10 mediated suppression.
  • This approach holds promise for treating Th2-dominated tumors, potentially in combination with other therapies.

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