Low-dose carboplatin reprograms tumor immune microenvironment through STING signaling pathway and synergizes with PD-1 inhibitors in lung cancer. (1st March 2021)

• Record Type: Journal Article
• Authors: Zhou, Li; Xu, Qiuli; Huang, Litang; Jin, Jiajia; Zuo, Xueying; Zhang, Qun; Ye, Liang; Zhu, Suhua; Zhan, Ping; Ren, Jianan; Lv, Tangfeng; Song, Yong
• Is Part Of: Cancer letters. Volume 500(2021)
• Page Start: 163
• Page End: 171
• Publication Date: 2021-03-01
• Subjects: Tmem173 -- Immune checkpoint inhibitors -- Safety -- Chemotherapy -- Synergy; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.11.049
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Although the combination of chemotherapy and immunotherapy is a hot topic in lung cancer, little is understood regarding the possible mechanisms behind their synergy. Moreover, safety is a major concern for clinicians while performing chemotherapy. Therefore, it is important to determine the appropriate dose and period of chemotherapy for combining it with immunotherapy, and investigate the underlying synergistic mechanism. Here, we showed that carboplatin can induce DNA damage and activate the canonical STING/TBK1/IRF3 pathway and non-canonical STING-NF-κB signaling complex. Further, low-dose carboplatin changed the "cold" tumor into a "hot" tumor via the signaling hub STING, augmenting CD8 + T-cell infiltration, increasing PD-L1 expression, and hence potentiating the anti-tumor effect of PD-1 inhibitors; importantly, there were no adverse effects. Furthermore, knocking down STING in tumor cells effectively reversed PD-L1 upregulation and STING pathway activation, and reduced the anti-tumor effect of low-dose carboplatin and carboplatin-PD-1 inhibitor combination. Our findings collectively reported a previously unexplored role of low-dose carboplatin targeting in the STING pathway and provided an economical, useful and safe option for improving the efficacy of PD-1 inhibitors in lung cancer. Highlights: Low-dose carboplatin increases CD8 + T cell infiltration and PD-L1 expression. Low-dose carboplatin is safe and turns a "cold" tumor into a "hot" tumor. Low-dose carboplatin potentiates the anti-tumor effect of PD-1 inhibitors. Carboplatin induces DNA Damage and activates the STING signaling pathway. STING knockdown in tumor reverses the anti-tumor effect of low-dose carboplatin.