Timing Anti-PD-L1 Checkpoint Blockade Immunotherapy to Enhance Tumor Irradiation

被引:0
作者
Lee, Steve Seung-Young [1 ]
Pagacz, Joanna [2 ]
Averbek, Sera [2 ]
Scholten, David [2 ]
Liu, Yue [2 ]
Kron, Stephen J. [2 ]
机构
[1] Univ Illinois, Coll Pharm, Dept Pharmaceut Sci, Chicago, IL 60612 USA
[2] Univ Chicago, Dept Mol Genet & Cell Biol, Chicago, IL 60637 USA
关键词
immune checkpoint inhibitor; radiotherapy/radioimmunotherapy; combination immunotherapy; ACQUIRED-RESISTANCE; RADIOTHERAPY; RADIATION; CANCER;
D O I
10.3390/cancers17030391
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: The ability of radiotherapy (RT) to drive anti-tumor immunity is limited by adaptive resistance. While RT induces inflammation and recruits activated tumor-infiltrating lymphocytes (TILs), including cytotoxic T lymphocytes (CTLs), the resulting radiation- and IFN gamma-dependent PD-L1 expression restores an immunosuppressed tumor microenvironment. Unleashing an effective anti-tumor response may require the precise sequencing of RT and checkpoint blockade immunotherapy (CBI) to block PD-L1 signaling before it can mediate its suppressive effects. Methods: Flank tumors formed in BALB/c mice with syngeneic CT26 colon or 4T1 mammary carcinoma cells were treated with otherwise ineffective doses of ionizing radiation (10 Gy) followed by CBI (0.2 mg anti-PD-L1, i.v.) after 0, 1, 3, 5, or 7 days, comparing tumor response. Anti-PD-L1 delivery was measured by fluorescence, TILs by flow cytometry and immunofluorescence, PD-L1 expression by immunohistochemistry, and tumor size by calipers. Results: In both CT26 and 4T1 tumors, 10 Gy alone resulted in a transient growth delay associated with infiltrating CTLs peaking at 3 days and PD-L1 at 5 days. CTLs returned to baseline after 7 days, consistent with adaptive resistance. Anti-PD-L1 failed to potentiate radiation except when injected 5 days after 10 Gy, which prevented CTL depletion and led to tumor elimination. Potentially contributing to compound effects, anti-PD-L1 penetrated tumors and bound PD-L1 more efficiently after irradiation. Conclusions: Optimal timing to exploit radiation-induced permeability to enhance CBI delivery and interrupt adaptive resistance by blocking PD-L1 as it peaks may offer a general strategy to enhance external beam radiotherapy by protecting activated TILs and potentiating anti-tumor immune response.
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页数:13
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