期刊
ISCIENCE
卷 24, 期 1, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2020.102016
关键词
-
资金
- US National Institutes of Health [R01CA160331, R01CA163377, R01CA202919, R01CA239128, R01CA243142, P01AG031862, P50CA228991]
- US Department of Defense [OC180109, OC190181]
- Honorable Tina Brozman Foundation for Ovarian Cancer Research
- Tina Brozman Ovarian Cancer Research Consortium 2.0
- Ovarian Cancer Research Alliance [596552]
- Cancer Center Support Grant (CCSG) [CA010815]
The study demonstrates that adoptive transfer of SASP-boosted therapy-induced senescent cells can enhance the sensitivity of ovarian tumors to immune checkpoint blockade and improve survival rates. The synergy between cisplatin-induced SASP and topoisomerase 1 (TOP1) inhibitors enhances this effect.
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 ex vivo 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.
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