Tumour-targeted interleukin-12 and entinostat combination therapy improves cancer survival by reprogramming the tumour immune cell landscape

Kristin C. Hicks, Paul L. Chariou, Yohei Ozawa, Christine M. Minnar, Karin M. Knudson, Thomas J. Meyer, Jing Bian, Margaret Cam, Jeffrey Schlom () and Sofia R. Gameiro
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Kristin C. Hicks: National Institutes of Health
Paul L. Chariou: National Institutes of Health
Yohei Ozawa: National Institutes of Health
Christine M. Minnar: National Institutes of Health
Karin M. Knudson: National Institutes of Health
Thomas J. Meyer: National Institutes of Health
Jing Bian: National Institutes of Health
Margaret Cam: National Institutes of Health
Jeffrey Schlom: National Institutes of Health
Sofia R. Gameiro: National Institutes of Health

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25393-x

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