期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 46, 期 -, 页码 210-219出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.intimp.2017.03.015
关键词
PD-1; PD-L1; Checkpoint inhibitors; Primary resistance; Acquired resistance
资金
- National Natural Science Foundation of China [81472843]
- Science and Technology Commission of Shanghai Municipality [14ZR1424700]
PD-1/PD-L1 blockade appears to be a very promising immunotherapy with significant clinical benefits and durable responses in multiple tumor types. However, the effectual clinical benefits of PD-1/PD-L1 blockade are hampered by a high rate of primary resistance, where patients do not respond to PD-1/PD-L1 blockade initially. And more distressingly, most patients eventually develop acquired resistance after an initial response to PD-1/PD-L1 blockade. The mechanisms underlying primary and acquired resistance to PD-1/PD-L1 blockade have remained ambiguous. This review documents in detail the current understanding of the mechanisms through which resistance to anti-PID1/PD-L1 therapy occurs. The mechanisms underlying primary resistance to PD-1/PD-L1 blockade contain several immunoregulatory factors affecting tumor-specific immune responses within the immune microenvironment, co-enrichment of a group of 26 transcriptomic signatures (named innate anti-PD-1 resistance (IPRES) signatures) and cancer-cell-autonomous cues. The mechanism attributable to acquired resistance harbors evolution of neoantigen landscape, mutations of JAIL and beta-2-microglobulin, and epigenetic stability of exhausted T cells. At last, the promising therapeutic strategies to sensitize the resistant patients are also briefly discussed. (C) 2017 Elsevier B.V. All rights reserved.
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