title: CXCL11-Armed oncolytic poxvirus elicits potent antitumor immunity and shows enhanced therapeutic efficacy.
abstract: We have armed a tumor-selective oncolytic vaccinia virus (vvDD) with the chemokine (CK) CXCL11, in order to enhance its ability to attract CXCR3+antitumor CTLs and possibly NK cells to the tumor microenvironment (TME) and improve its therapeutic efficacy. As expected, vvDD-CXCL11 attracted high numbers of tumor-specific T cells to the TME in a murine AB12 mesothelioma model. Intratumoral virus-directed CXCL11 expression enhanced local numbers of CD8+CTLs and levels of granzyme B, while reducing expression of several suppressive molecules, TGF-β, COX2, and CCL22 in the TME. Unexpectedly, we observed that vvDD-CXCL11, but not parental vvDD, induced a systemic increase in tumor-specific IFNγ-producing CD8+T cells in the spleen and other lymph organs, indicating the induction of systemic antitumor immunity. This effect was associated with enhanced therapeutic efficacy and a survival benefit in tumor-bearing mice treated with vvDD-CXCL11, mediated by CD8+T cells and IFNγ, but not CD4+T cells. These results demonstrate that intratumoral expression of CXCL11, in addition to promoting local trafficking of T cells and to a lesser extent NK cells, has a novel function as a factor eliciting systemic immunity to cancer-associated antigens. Our data provide a rationale for expressing CXCL11 to enhance the therapeutic efficacy of oncolytic viruses (OVs) and cancer vaccines.
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Zuqiang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Roshni
authors.initials: R
authors.lastname: Ravindranathan
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA; Immunology, University of Pittsburgh, Pittsburgh, PA, USA; Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Z Sheng
authors.initials: ZS
authors.lastname: Guo
authors.affiliation: The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
keywords: Antitumor immunity; CD8+ T cells; IFNγ; chemokine; oncolytic virus; therapeutic efficacy; tumor microenvironment