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Vesicular stomatitis virus-induced immune suppressor cells generate antagonism between intratumoral oncolytic virus

Candice Willmon1, Rosa M Diaz, Phonphimon Wongthida

  • 1Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|October 28, 2010
PubMed

Insights

Cyclophosphamide (CPA) shows significant antitumor effects against mesothelioma by engaging CD4 T cells and NK cells. However, combining CPA with vesicular stomatitis virus (VSV) unexpectedly reduces efficacy due to VSV-induced immune suppression.

Area of Science:

  • Immunology
  • Oncology
  • Virology

Background:

  • Oncolytic viruses like vesicular stomatitis virus (VSV) show in vitro efficacy but limited in vivo therapeutic effects in established tumors.
  • Systemic cyclophosphamide (CPA) demonstrates significant antitumor activity in the AE17ova mesothelioma mouse model.

Purpose of the Study:

  • To investigate the therapeutic effects and immune interactions of combining CPA with VSV in established AE17ova mesothelioma tumors.
  • To elucidate the mechanisms underlying the observed synergistic or antagonistic effects of CPA and VSV combination therapy.

Main Methods:

  • Intratumoral injection of VSV and systemic administration of CPA in C57Bl/6 mice bearing AE17ova mesothelioma tumors.
  • Assessment of tumor growth, intratumoral VSV titers, and immune cell populations (CD4 T cells, NK cells, CD11b(+)GR-1(+) cells).
  • Evaluation of T-cell activation and NK cell-mediated cytotoxicity in the presence of VSV and CPA.

Main Results:

  • CPA alone mediated significant antitumor effects dependent on CD4 T cells and NK cells.
  • Combination therapy of CPA and VSV reduced therapeutic efficacy compared to CPA alone, despite increased intratumoral VSV.
  • Intratumoral VSV induced transforming growth factor-β (TGF-β)-dependent suppression by CD11b(+)GR-1(+) cells, inhibiting T-cell activation and NK cell-dependent tumor cell killing.

Conclusions:

  • Oncolytic virus treatment can elicit complex immune-mediated consequences in vivo, with both beneficial and detrimental effects on antitumor therapy.
  • The combination of VSV with CPA can lead to unexpected negative impacts on therapeutic efficacy due to virus-induced immune suppression.
  • Understanding these immune consequences is crucial for optimizing combination virotherapy strategies with other immunomodulatory agents.

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