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在临床前鳞状细胞癌模型中，瘤内注射STING激动剂联合抗程序性死亡蛋白1阻断抗体诱导肿瘤消退。

Induction of tumor regression by intratumoral STING agonists combined with anti-programmed death-L1 blocking antibody in a preclinical squamous cell carcinoma model.

作者信息

Gadkaree Shekhar K, Fu Juan, Sen Rupashree, Korrer Michael J, Allen Clint, Kim Young J

机构信息

Department of Otolaryngology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.

Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

出版信息

Head Neck. 2017 Jun;39(6):1086-1094. doi: 10.1002/hed.24704. Epub 2017 Mar 21.

DOI:10.1002/hed.24704
PMID:28323387
Abstract

BACKGROUND

Cyclic dinucleotides (CDNs) are bacterial intracellular messengers that have demonstrated antitumor activity in melanoma and breast tumors, although their role in immunotherapy of head and neck squamous cell cancers (HNSCCs) has not been well investigated.

METHODS

We measured primary tumor growth rates, mechanism of antitumor activity, and efficacy of programmed death-L1 blockade combinatorial therapy in SCCFVII tumor-bearing C3H/HeOUJ mice undergoing intratumoral injections with RR-cyclic-di-guanine (synthetic CDG), CDG (natural cyclic-di-guanine), R848 (TLR 7/8 agonist), or phosphate buffered saline (PBS, control).

RESULTS

Intratumoral CDN treatment groups showed decreased tumor size and enhanced splenocyte Th1 response when compared to the PBS treatment control group (p < .05). The RR-CDG tumor microenvironment showed upregulated interferon (IFN)-γ+CD8+ and programmed death-L1. Combining programmed death-L1 blocking antibody with RR-CDG induced regression of established tumors.

CONCLUSION

This study demonstrates the antitumor effects of CDNs in a HNSCC cell line. These preclinical data strongly support the future clinical development of intratumoral CDN in patients with HNSCC. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1086-1094, 2017.

摘要

背景

环二核苷酸（CDNs）是细菌细胞内信使，已在黑色素瘤和乳腺肿瘤中显示出抗肿瘤活性，但其在头颈部鳞状细胞癌（HNSCCs）免疫治疗中的作用尚未得到充分研究。

方法

我们在携带SCCFVII肿瘤的C3H/HeOUJ小鼠中，通过瘤内注射RR-环二鸟苷（合成CDG）、CDG（天然环二鸟苷）、R848（Toll样受体7/8激动剂）或磷酸盐缓冲盐水（PBS，对照），测量原发性肿瘤生长速率、抗肿瘤活性机制以及程序性死亡蛋白1（PD-L1）阻断联合疗法的疗效。

结果

与PBS治疗对照组相比，瘤内CDN治疗组的肿瘤大小减小，脾细胞Th1反应增强（p <.05）。RR-CDG肿瘤微环境显示干扰素（IFN）-γ+CD8+和程序性死亡蛋白1上调。将程序性死亡蛋白1阻断抗体与RR-CDG联合使用可使已形成的肿瘤消退。

结论

本研究证明了CDNs在HNSCC细胞系中的抗肿瘤作用。这些临床前数据有力地支持了瘤内CDN在HNSCC患者中的未来临床开发。©2017威利期刊公司。《头颈》39: 1086 - 1094, 2017。

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