Liu Zuqiang, Ravindranathan Roshni, Li Jun, Kalinski Pawel, Guo Z Sheng, Bartlett David L
The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
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.
Oncoimmunology. 2015 Oct 29;5(3):e1091554. doi: 10.1080/2162402X.2015.1091554. eCollection 2016 Mar.
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.
我们用趋化因子（CK）CXCL11武装了一种肿瘤选择性溶瘤痘苗病毒（vvDD），以增强其吸引CXCR3抗肿瘤细胞毒性T淋巴细胞（CTL）以及可能还有自然杀伤细胞（NK细胞）至肿瘤微环境（TME）的能力，并提高其治疗效果。正如预期的那样，在小鼠AB12间皮瘤模型中，vvDD-CXCL11吸引了大量肿瘤特异性T细胞至TME。瘤内病毒介导的CXCL11表达增加了局部CD8 CTL数量和颗粒酶B水平，同时降低了TME中几种抑制性分子TGF-β、COX2和CCL22的表达。出乎意料的是，我们观察到vvDD-CXCL11而非亲本vvDD诱导脾脏和其他淋巴器官中肿瘤特异性产生IFNγ的CD8 T细胞出现全身性增加，这表明诱导了全身性抗肿瘤免疫。这种效应与用vvDD-CXCL11治疗的荷瘤小鼠的治疗效果增强和生存获益相关，其由CD8 T细胞和IFNγ介导，而非CD4 T细胞。这些结果表明，CXCL11在瘤内的表达，除了促进T细胞以及在较小程度上促进NK细胞的局部募集外，还具有作为引发针对癌症相关抗原的全身性免疫的因子的新功能。我们的数据为表达CXCL11以增强溶瘤病毒（OV）和癌症疫苗的治疗效果提供了理论依据。
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