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Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11774-9. doi: 10.1073/pnas.1410626111. Epub 2014 Jul 28.

Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells.

Author information

1
Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center.
2
Oncology Flow Cytometry Core Facility, and.
3
Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center,Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287 bertvog@gmail.com sbzhou@jhmi.edu.
4
Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, bertvog@gmail.com sbzhou@jhmi.edu.

Abstract

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.

KEYWORDS:

5-azacytidine; HDAC; entinostat; exome; methyltransferase

PMID:
25071169
PMCID:
PMC4136565
DOI:
10.1073/pnas.1410626111
[Indexed for MEDLINE]
Free PMC Article

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