Multifaceted therapeutic targeting of ovarian peritoneal carcinomatosis through virus-induced immunomodulation

Shashi Gujar, Rebecca Dielschneider, Derek Clements, Erin Helson, Maya Shmulevitz, Paola Marcato, Da Pan, Lu Zhe Pan, Dae Gyun Ahn, Abdulaziz Alawadhi, Patrick W.K. Lee

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)

Abstract

Immunosuppression associated with ovarian cancer (OC) and resultant peritoneal carcinomatosis (PC) hampers the efficacy of many promising treatment options, including immunotherapies. It is hypothesized that oncolytic virus-based therapies can simultaneously kill OC and mitigate immunosuppression. Currently, reovirus-based anticancer therapy is undergoing phase I/II clinical trials for the treatment of OC. Hence, this study was focused on characterizing the effects of reovirus therapy on OC and associated immune microenvironment. Our data shows that reovirus efficiently killed OC cells and induced higher expression of the molecules involved in antigen presentation including major histocompatibility complex (MHC) class I, β2-microglobulin (β2M), TAP-1, and TAP-2. In addition, in the presence of reovirus, dendritic cells (DCs) overcame the OC-mediated phenotypic suppression and successfully stimulated tumor-specific CD8+ T cells. In animal studies, reovirus targeted local and distal OC, alleviated the severity of PC and significantly prolonged survival. These therapeutic effects were accompanied by decreased frequency of suppressive cells, e.g., Gr1.1+, CD11b+ myeloid derived suppressor cells (MDSCs), and CD4+, CD25+, FOXP3+ Tregs, tumor-infiltration of CD3+ cells and higher expression of Th1 cytokines. Finally, reovirus therapy during early stages of OC also resulted in the postponement of PC development. This report elucidates timely information on a therapeutic approach that can target OC through clinically desired multifaceted mechanisms to better the outcomes.

Original languageEnglish
Pages (from-to)338-347
Number of pages10
JournalMolecular Therapy
Volume21
Issue number2
DOIs
Publication statusPublished - Feb 2013

Bibliographical note

Funding Information:
This work was supported by an operating grant from the Canadian Institutes for Health Research to P.W.K.L. D.C. and E.H. received the Norah Stephen Summer Studentship, while D.-G.A. holds the postdoctoral fellowship from the Beatrice Hunter Cancer Research Institute. S.G. is funded by the Canadian Institutes for Health Research postdoctoral fellowship. The authors declared no conflict of interest.

ASJC Scopus Subject Areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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