Liu Zuqiang, Hao Xingxing, Zhang Yi, Zhang Jiying, Carey Cara D, Falo Louis D, Storkus Walter J, You Zhaoyang
Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Oncoimmunology. 2017 Apr 24;6(6):e1315487. doi: 10.1080/2162402X.2017.1315487. eCollection 2017.
The progressive tumor microenvironment (TME) coordinately supports tumor cell expansion and metastasis, while it antagonizes the survival and (poly-)functionality of antitumor T effector cells. There remains a clear need to develop novel therapeutic strategies that can transform the TME into a pro-inflammatory niche that recruits and sustains protective immune cell populations. While intravenous treatment with tumor-primed CD4 T cells combined with intraperitoneal delivery of agonist anti-glucocorticoid-induced TNF receptor (α-GITR) mAb results in objective antitumor responses in murine early stage disease models, this approach is ineffective against more advanced tumors. Further subcutaneous co-administration of a vaccine consisting of tumor antigen-loaded dendritic cells (DC) failed to improve the antitumor efficacy of this approach. Remarkably, these same three therapeutic agents elicited significant antitumor benefits when the antitumor CD4 T cells and tumor antigen-loaded DC were co-injected directly into tumors along with intratumoral or intraperitoneal delivery of α-GITR mAb. This latter protocol induced the production of an array of antitumor cytokines and chemokines within the TME, supporting increased tumor-infiltration by antitumor CD8 T cells capable of mediating tumor regression and extended overall survival.
进行性肿瘤微环境（TME）协同支持肿瘤细胞的增殖和转移，同时对抗抗肿瘤T效应细胞的存活和（多）功能。显然，仍需要开发新的治疗策略，将TME转化为促炎性微环境，以募集和维持保护性免疫细胞群体。虽然在小鼠早期疾病模型中，用肿瘤致敏的CD4 T细胞进行静脉内治疗并联合腹腔内递送激动剂抗糖皮质激素诱导的TNF受体（α-GITR）单克隆抗体可产生客观的抗肿瘤反应，但这种方法对更晚期肿瘤无效。进一步皮下联合给予由负载肿瘤抗原的树突状细胞（DC）组成的疫苗，未能提高该方法的抗肿瘤疗效。值得注意的是，当将抗肿瘤CD4 T细胞和负载肿瘤抗原的DC与肿瘤内或腹腔内递送的α-GITR单克隆抗体一起直接注射到肿瘤中时，这三种治疗剂同样产生了显著的抗肿瘤益处。后一种方案诱导了TME内一系列抗肿瘤细胞因子和趋化因子的产生，支持能够介导肿瘤消退的抗肿瘤CD8 T细胞增加肿瘤浸润，并延长总体生存期。
