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

Fingerprint

Myeloid Cells
CTLA-4 Antigen
Neoplasms
Epigenomics
Cell Death
Antibodies
Phosphatidylinositol 3-Kinases
Immunotherapy
Pharmaceutical Preparations
Myeloid-Derived Suppressor Cells

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. / Kim, Kibem; Skora, Andrew D.; Li, Zhaobo; Liu, Qiang; Tam, Ada J.; Blosser, Richard L.; Diaz, Luis A.; Papadopoulos, Nickolas; Kinzler, Kenneth W; Vogelstein, Bert; Zhou, Shibin.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 32, 12.08.2014, p. 11774-11779.

Research output: Contribution to journalArticle

@article{8c8ee4e03264438986ad24bb3293c5ad,
title = "Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells",
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, Entinostat, Exome, HDAC, Methyltransferase",
author = "Kibem Kim and Skora, {Andrew D.} and Zhaobo Li and Qiang Liu and Tam, {Ada J.} and Blosser, {Richard L.} and Diaz, {Luis A.} and Nickolas Papadopoulos and Kinzler, {Kenneth W} and Bert Vogelstein and Shibin Zhou",
year = "2014",
month = "8",
day = "12",
doi = "10.1073/pnas.1410626111",
language = "English (US)",
volume = "111",
pages = "11774--11779",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "32",

}

TY - JOUR

T1 - Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells

AU - Kim, Kibem

AU - Skora, Andrew D.

AU - Li, Zhaobo

AU - Liu, Qiang

AU - Tam, Ada J.

AU - Blosser, Richard L.

AU - Diaz, Luis A.

AU - Papadopoulos, Nickolas

AU - Kinzler, Kenneth W

AU - Vogelstein, Bert

AU - Zhou, Shibin

PY - 2014/8/12

Y1 - 2014/8/12

N2 - 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.

AB - 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.

KW - 5-azacytidine

KW - Entinostat

KW - Exome

KW - HDAC

KW - Methyltransferase

UR - http://www.scopus.com/inward/record.url?scp=84905994658&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905994658&partnerID=8YFLogxK

U2 - 10.1073/pnas.1410626111

DO - 10.1073/pnas.1410626111

M3 - Article

C2 - 25071169

AN - SCOPUS:84905994658

VL - 111

SP - 11774

EP - 11779

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 32

ER -