Consequences of the perivascular niche remodeling for tumoricidal T-cell trafficking into metastasis of ovarian cancer.

Aberrant angiogenesis in ovarian cancer (OC), driven by excessive vascular endothelial growth factor (VEGF) and other proangiogenic mediators, gives rise to structurally and functionally abnormal tumor vasculature that hinders effective T-cell infiltration. To overcome these barriers, we investigated how modulation of the perivascular niche influences antitumor T-cell trafficking and function in OC. T cells expressing a rearranged TCR transgene specific for SV40 T antigen (TAG) were adoptively transferred into TAG+ MOVCAR 5009 ovarian tumor-bearing SCID mice or syngeneic TgMISIIR-TAg-Low transgenic mice, which express TAG as a self-antigen in the fallopian tube epithelium. Transfers were performed either alone or following treatment with an oncolytic vaccinia virus expressing a CXCR4 antagonist (OV-CXCR4-A) or a control virus (OV-Fc). Compared with OV-Fc, OV-CXCR4-A treatment remodeled the tumor vasculature, inhibited recruitment of VEGF-producing myeloid-derived suppressor cells, and disrupted the proangiogenic microenvironment. These changes enhanced infiltration of adoptively transferred TCRTAG T cells within the perivascular niche, correlating with improved antitumor activity and survival. Collectively, our findings demonstrate that CXCR4 blockade-mediated reprogramming of the perivascular tumor microenvironment promotes effective T-cell trafficking and function, providing a mechanistic rationale for combining oncolytic virotherapy with adoptive cell transfer in OC.