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

doi:10.1038/mt.2012.228

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 journal › Article › peer-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 language	English
Pages (from-to)	338-347
Number of pages	10
Journal	Molecular Therapy
Volume	21
Issue number	2
DOIs	https://doi.org/10.1038/mt.2012.228
Publication status	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/mt.2012.228

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@article{62515039cf5f4436a9734ab3007858e4,

title = "Multifaceted therapeutic targeting of ovarian peritoneal carcinomatosis through virus-induced immunomodulation",

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.",

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

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.",

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doi = "10.1038/mt.2012.228",

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AU - Gujar, Shashi

AU - Dielschneider, Rebecca

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AU - Shmulevitz, Maya

AU - Marcato, Paola

AU - Pan, Da

AU - Pan, Lu Zhe

AU - Ahn, Dae Gyun

AU - Alawadhi, Abdulaziz

AU - Lee, Patrick W.K.

N1 - 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.

PY - 2013/2

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

UN SDGs

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