TY - JOUR
T1 - Oncolytic α-herpesvirus and myeloid-tropic cytomegalovirus cooperatively enhance systemic antitumor responses
AU - Jiang, Haifei
AU - Nace, Rebecca
AU - Ariail, Emily
AU - Ma, Yejun
AU - McGlinch, Erin
AU - Ferguson, Coryn
AU - Fernandez Carrasco, Talia
AU - Packiriswamy, Nandakumar
AU - Zhang, Lianwen
AU - Peng, Kah Whye
AU - Russell, Stephen J.
N1 - Publisher Copyright:
© 2023 The American Society of Gene and Cell Therapy
PY - 2024/1/3
Y1 - 2024/1/3
N2 - Oncolytic virotherapy aims to activate host antitumor immunity. In responsive tumors, intratumorally injected herpes simplex viruses (HSVs) have been shown to lyse tumor cells, resulting in local inflammation, enhanced tumor antigen presentation, and boosting of antitumor cytotoxic lymphocytes. In contrast to HSV, cytomegalovirus (CMV) is nonlytic and reprograms infected myeloid cells, limiting their antigen-presenting functions and protecting them from recognition by natural killer (NK) cells. Here, we show that when co-injected into mouse tumors with an oncolytic HSV, mouse CMV (mCMV) preferentially targeted tumor-associated myeloid cells, promoted the local release of proinflammatory cytokines, and enhanced systemic antitumor immune responses, leading to superior control of both injected and distant contralateral tumors. Deletion of mCMV genes m06, which degrades major histocompatibility complex class I (MHC class I), or m144, a viral MHC class I homolog that inhibits NK activation, was shown to diminish the antitumor activity of the HSV/mCMV combination. However, an mCMV recombinant lacking the m04 gene, which escorts MHC class I to the cell surface, showed superior HSV adjuvanticity. CMV is a potentially promising agent with which to reshape and enhance antitumor immune responses following oncolytic HSV therapy.
AB - Oncolytic virotherapy aims to activate host antitumor immunity. In responsive tumors, intratumorally injected herpes simplex viruses (HSVs) have been shown to lyse tumor cells, resulting in local inflammation, enhanced tumor antigen presentation, and boosting of antitumor cytotoxic lymphocytes. In contrast to HSV, cytomegalovirus (CMV) is nonlytic and reprograms infected myeloid cells, limiting their antigen-presenting functions and protecting them from recognition by natural killer (NK) cells. Here, we show that when co-injected into mouse tumors with an oncolytic HSV, mouse CMV (mCMV) preferentially targeted tumor-associated myeloid cells, promoted the local release of proinflammatory cytokines, and enhanced systemic antitumor immune responses, leading to superior control of both injected and distant contralateral tumors. Deletion of mCMV genes m06, which degrades major histocompatibility complex class I (MHC class I), or m144, a viral MHC class I homolog that inhibits NK activation, was shown to diminish the antitumor activity of the HSV/mCMV combination. However, an mCMV recombinant lacking the m04 gene, which escorts MHC class I to the cell surface, showed superior HSV adjuvanticity. CMV is a potentially promising agent with which to reshape and enhance antitumor immune responses following oncolytic HSV therapy.
KW - MHC class I manipulating gene
KW - antitumor immune responses
KW - cytomegalovirus
KW - major histocompatibility complex class I
KW - oncolytic herpesvirus
KW - tumor microenvironment
KW - tumor-associated myeloid cells
UR - http://www.scopus.com/inward/record.url?scp=85176761452&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85176761452&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2023.11.003
DO - 10.1016/j.ymthe.2023.11.003
M3 - Article
C2 - 37927036
AN - SCOPUS:85176761452
SN - 1525-0016
VL - 32
SP - 241
EP - 256
JO - Molecular Therapy
JF - Molecular Therapy
IS - 1
ER -