Oncolytic α-herpesvirus and myeloid-tropic cytomegalovirus cooperatively enhance systemic antitumor responses

Abstract

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 CTLs. 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 cells. Here we show that, when coinjected into mouse tumors with an oncolytic HSV, mouse CMV (mCMV) preferentially targeted tumor-associated myeloid cells, promoted the local release of pro-inflammatory 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 MHC-I, or m144, a viral MHC-I homolog that inhibits NK activation, was shown to diminish the antitumor activity of the HSV/mCMV combination. However, a mCMV recombinant lacking the m04 gene which escorts MHC-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.