Oncolytic HSV virotherapy in murine sarcomas differentially triggers an antitumor T-cell response in the absence of virus permissivity.
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.
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA; Medical Scientist Training Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA; Immunobiology Graduate Training Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
Jennifer L
JL
Leddon
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University , Columbus, Ohio, USA.
Chun-Yu
CY
Chen
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University , Columbus, Ohio, USA.
Mark A
MA
Currier
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University , Columbus, Ohio, USA.
Pin-Yi
PY
Wang
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University , Columbus, Ohio, USA.
Francesca A
FA
Jung
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University , Columbus, Ohio, USA.
Nicholas L
NL
Denton
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University , Columbus, Ohio, USA.
Kevin M
KM
Cripe
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA; Division of Hematology/Oncology/Blood and Marrow Transplantation, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Kellie B
KB
Haworth
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, The Ohio State University , Columbus, Ohio, USA.
Michael A
MA
Arnold
Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, The Ohio State University , Columbus, Ohio, USA.
Amy C
AC
Gross
Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, The Ohio State University , Columbus, Ohio, USA.
Timothy D
TD
Eubank
Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine , Pittsburgh, Pennsylvania, USA.
William F
WF
Goins
Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine , Pittsburgh, Pennsylvania, USA.
Joseph C
JC
Glorioso
Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine , Pittsburgh, Pennsylvania, USA.
Justus B
JB
Cohen
Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine , Pittsburgh, Pennsylvania, USA.
Paola
P
Grandi
Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati , Cincinnati, Ohio, USA.
David A
DA
Hildeman
Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA; Division of Hematology/Oncology/Blood and Marrow Transplantation, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio, USA.
Timothy P
TP
Cripe