期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 32, 页码 11774-11779出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1410626111
关键词
5-azacytidine; entinostat; methyltransferase; HDAC; exome
资金
- The Virginia and D. K. Ludwig Fund for Cancer Research
- BioMed Valley Discoveries
- National Institutes of Health [CA062924, CA043460]
Impressive responses have been observed in patients treated with checkpoint inhibitory anti-programmed cell death-1 (PD-1) or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies. However, immunotherapy against poorly immunogenic cancers remains a challenge. Here we report that treatment with both anti-PD-1 and anti-CTLA-4 antibodies was unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors. Cotreatment with epigenetic-modulating drugs and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of the tumor-bearing mice. Functional studies revealed that the primary targets of the epigenetic modulators were myeloid-derived suppressor cells (MDSCs). A PI3K inhibitor that reduced circulating MDSCs also eradicated 4T1 tumors in 80% of the mice when combined with immune checkpoint inhibitors. Thus, cancers resistant to immune checkpoint blockade can be cured by eliminating MDSCs.
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