Hao Xue, Zhao Bo, Zhou Wei, Liu Heng, Fukumoto Takeshi, Gabrilovich Dmitry, Zhang Rugang
Immunology, Metastasis and Microenvironment Program, The Wistar Institute, Philadelphia, PA 19104, USA.
AstraZeneca, Oncology R&D, Gaithersburg, MD 20878, USA.
iScience. 2020 Dec 30;24(1):102016. doi: 10.1016/j.isci.2020.102016. eCollection 2021 Jan 22.
Therapy-induced senescence-associated secretory phenotype (SASP) correlates with overcoming resistance to immune checkpoint blockade (ICB). Intrinsic resistance to ICB is a major clinical challenge. For example, ovarian cancer is largely resistant to ICB. Here we show that adoptive transfer of SASP-boosted therapy-induced senescent cells sensitizes ovarian tumor to ICB. Topoisomerase 1 (TOP1) inhibitors such as irinotecan enhance cisplatin-induced SASP, which depends on the TOP1 cleavage complex-regulated cGAS pathway. Significantly, intraperitoneal transfer of cisplatin-induced, SASP-boosted senescent cells with irinotecan sensitizes ovarian tumor to anti-PD-1 antibody and improves the survival of tumor-bearing mice in an immunocompetent, syngeneic model. This correlates with the infiltration of transferred senescent cells in the established orthotopic tumors and an increase in the infiltration of activated CD8 T cells and dendritic cells in the tumor bed. Our findings indicate that adoptive transfer of SASP-boosted therapy-induced senescent cells represents a potential therapeutic strategy to sensitize tumors to ICB.
治疗诱导的衰老相关分泌表型（SASP）与克服免疫检查点阻断（ICB）耐药性相关。ICB的内在耐药性是一个主要的临床挑战。例如，卵巢癌对ICB大多耐药。在此我们表明，过继转移经SASP增强的治疗诱导衰老细胞可使卵巢肿瘤对ICB敏感。拓扑异构酶1（TOP1）抑制剂如伊立替康可增强顺铂诱导的SASP，这依赖于TOP1切割复合物调节的cGAS途径。重要的是，在免疫健全的同基因模型中，经伊立替康处理的顺铂诱导的、SASP增强的衰老细胞腹腔内转移可使卵巢肿瘤对抗PD-1抗体敏感，并提高荷瘤小鼠的存活率。这与转移的衰老细胞在已建立的原位肿瘤中的浸润以及肿瘤床中活化的CD8 T细胞和树突状细胞浸润增加相关。我们的研究结果表明，过继转移经SASP增强的治疗诱导衰老细胞代表了一种使肿瘤对ICB敏感的潜在治疗策略。
