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

doi:10.1073/pnas.1410626111

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

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344 Scopus citations

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 language	English (US)
Pages (from-to)	11774-11779
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	111
Issue number	32
DOIs	https://doi.org/10.1073/pnas.1410626111
State	Published - Aug 12 2014

Keywords

5-azacytidine
Entinostat
Exome
HDAC
Methyltransferase

ASJC Scopus subject areas

General

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10.1073/pnas.1410626111

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Kim, K., Skora, A. D., Li, Z., Liu, Q., Tam, A. J., Blosser, R. L., Diaz, L. A., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., & Zhou, S. (2014). Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proceedings of the National Academy of Sciences of the United States of America, 111(32), 11774-11779. https://doi.org/10.1073/pnas.1410626111

Kim, K, Skora, AD, Li, Z, Liu, Q, Tam, AJ, Blosser, RL, Diaz, LA, Papadopoulos, N , Kinzler, KW , Vogelstein, B & Zhou, S 2014, 'Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 32, pp. 11774-11779. https://doi.org/10.1073/pnas.1410626111

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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.",

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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

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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.

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

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