TY - JOUR
T1 - Tumour-targeted interleukin-12 and entinostat combination therapy improves cancer survival by reprogramming the tumour immune cell landscape
AU - Hicks, Kristin C.
AU - Chariou, Paul L.
AU - Ozawa, Yohei
AU - Minnar, Christine M.
AU - Knudson, Karin M.
AU - Meyer, Thomas J.
AU - Bian, Jing
AU - Cam, Margaret
AU - Schlom, Jeffrey
AU - Gameiro, Sofia R.
N1 - Funding Information:
The authors thank Curtis Randolph for his excellent technical assistance and Debra Weingarten for her editorial assistance in the preparation of this manuscript. The authors appreciate the technical support of Drs. Kimia Dadkhah and Michael Kelly, Center of Cancer Research Single Cell Analysis Facility (SCAF) in the scRNA sequencing. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health, and by Cooperative Research and Development Agreements (CRADAs) between the NCI and Syndax Pharmaceuticals, Inc., and the NCI and EMD Serono, Inc.
Publisher Copyright:
© 2021, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Poorly inflamed carcinomas do not respond well to immune checkpoint blockade. Converting the tumour microenvironment into a functionally inflamed immune hub would extend the clinical benefit of immune therapy to a larger proportion of cancer patients. Here we show, by using comprehensive single-cell transcriptome, proteome, and immune cell analysis, that Entinostat, a class I histone deacetylase inhibitor, facilitates accumulation of the necrosis-targeted recombinant murine immune-cytokine, NHS-rmIL12, in experimental mouse colon carcinomas and poorly immunogenic breast tumours. This combination therapy reprograms the tumour innate and adaptive immune milieu to an inflamed landscape, where the concerted action of highly functional CD8+ T cells and activated neutrophils drive macrophage M1-like polarization, leading to complete tumour eradication in 41.7%-100% of cases. Biomarker signature of favourable overall survival in multiple human tumor types shows close resemblance to the immune pattern generated by Entinostat/NHS-rmIL12 combination therapy. Collectively, these findings provide a rationale for combining NHS-IL12 with Entinostat in the clinical setting.
AB - Poorly inflamed carcinomas do not respond well to immune checkpoint blockade. Converting the tumour microenvironment into a functionally inflamed immune hub would extend the clinical benefit of immune therapy to a larger proportion of cancer patients. Here we show, by using comprehensive single-cell transcriptome, proteome, and immune cell analysis, that Entinostat, a class I histone deacetylase inhibitor, facilitates accumulation of the necrosis-targeted recombinant murine immune-cytokine, NHS-rmIL12, in experimental mouse colon carcinomas and poorly immunogenic breast tumours. This combination therapy reprograms the tumour innate and adaptive immune milieu to an inflamed landscape, where the concerted action of highly functional CD8+ T cells and activated neutrophils drive macrophage M1-like polarization, leading to complete tumour eradication in 41.7%-100% of cases. Biomarker signature of favourable overall survival in multiple human tumor types shows close resemblance to the immune pattern generated by Entinostat/NHS-rmIL12 combination therapy. Collectively, these findings provide a rationale for combining NHS-IL12 with Entinostat in the clinical setting.
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U2 - 10.1038/s41467-021-25393-x
DO - 10.1038/s41467-021-25393-x
M3 - Article
C2 - 34446712
AN - SCOPUS:85113592505
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5151
ER -
