Oncolytic HSV virotherapy in murine sarcomas differentially triggers an antitumor T-cell response in the absence of virus permissivity

被引:35
作者
Leddon, Jennifer L. [1 ,2 ,3 ]
Chen, Chun-Yu [1 ]
Currier, Mark A. [1 ]
Wang, Pin-Yi [1 ]
Jung, Francesca A. [1 ]
Denton, Nicholas L. [1 ]
Cripe, Kevin M. [1 ]
Haworth, Kellie B. [1 ,4 ]
Arnold, Michael A. [5 ]
Gross, Amy C. [6 ]
Eubank, Timothy D. [6 ]
Goins, William F. [7 ]
Glorioso, Joseph C. [7 ]
Cohen, Justus B. [7 ]
Grandi, Paola [7 ]
Hildeman, David A. [8 ]
Cripe, Timothy P. [1 ,4 ]
机构
[1] Ohio State Univ, Nationwide Childrens Hosp, Ctr Childhood Canc & Blood Dis, Columbus, OH 43210 USA
[2] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Med Scientist Training Program, Cincinnati, OH USA
[3] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Immunobiol Grad Training Program, Cincinnati, OH USA
[4] Ohio State Univ, Nationwide Childrens Hosp, Div Hematol Oncol Blood & Marrow Transplantat, Columbus, OH 43210 USA
[5] Ohio State Univ, Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH 43210 USA
[6] Ohio State Univ, Div Pulm Allergy Crit Care & Sleep Med, Columbus, OH 43210 USA
[7] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA
[8] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Div Cellular & Mol Immunol, Cincinnati, OH USA
来源
MOLECULAR THERAPY-ONCOLYTICS | 2015年 / 2卷
关键词
RHABDOMYOSARCOMA; INJECTION; VECTORS;
D O I
10.1038/mto.2014.10
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Multiple studies have indicated that in addition to direct oncolysis, virotherapy promotes an antitumor cytotoxic T cell response important for efficacy. To study this phenomenon further, we tested three syngeneic murine sarcoma models that displayed varied degrees of permissiveness to oncolytic herpes simplex virus replication and cytotoxicity in vitro, with the most permissive being comparable to some human sarcoma tumor lines. The in vivo antitumor effect ranged from no or modest response to complete tumor regression and protection from tumor rechallenge. The in vitro permissiveness to viral oncolysis was not predictive of the in vivo antitumor effect, as all three tumors showed intact interferon signaling and minimal permissiveness to virus in vivo. Tumor shrinkage was T-cell mediated with a tumor-specific antigen response required for maximal antitumor activity. Further analysis of the innate and adaptive immune microenvironment revealed potential correlates of susceptibility and resistance, including favorable and unfavorable cytokine profiles, differential composition of intratumoral myeloid cells, and baseline differences in tumor cell immunogenicity and tumor-infiltrating T-cell subsets. It is likely that a more complete understanding of the interplay between the immunologic immune microenvironment and virus infection will be necessary to fully leverage the antitumor effects of this therapeutic platform.
引用
收藏
页数:9
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