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

Kibem Kim, Andrew D. Skora, Zhaobo Li, Qiang Liu, Ada J. Tam, Richard L. Blosser, Luis A. Diaz, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Shibin Zhou

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)11774-11779
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number32
DOIs
StatePublished - Aug 12 2014

Keywords

  • 5-azacytidine
  • Entinostat
  • Exome
  • HDAC
  • Methyltransferase

ASJC Scopus subject areas

  • General

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