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Histone deacetylase inhibitors (HDACi) enhance phagocytosis of cancer cells

Combination of drugs increases response rate of a therapeutic agent
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(Vienna, 28 January 2020) In a new study, scientists from the Division of General Surgery, Department of Surgery and the Comprehensive Cancer Centre (CCC) of the MedUni Vienna and Vienna General Hospital have demonstrated that histone deacetylase inhibitors (HDACi) in combination with the agent trastuzumab can positively enhance the endogenous immune defence in the form of phagocytosis of breast cancer cells.

The study was conducted inter alia within the framework of the Ludwig Boltzmann Institute Applied Diagnostics (lbi:ad) and has now been published in the prestigious "Journal for ImmunoTherapy of Cancer“ (IF: 8,728).

Breast cancer is the second commonest form of cancer and the fifth commonest cause of death from cancer in women worldwide. In approximately 15-30% of patients the epidermal growth factor receptor 2 (HER2) is overexpressed, which in turn manifests itself in a more rapid tumour growth and tumour spread. One therapeutic approach is to give the antibody (protein molecule) trastuzumab, which blocks the HER2, thereby obstructing the growth-promoting signals of cancer cells. However, when trastuzumab is given as a monotherapy, the response rates only only range between19-26%. It is therefore all the more urgent to discover reinforcing therapeutic combinations to improve the response to trastuzumab.

Studies in cell lines and animal models have shown that one of the main modes of action of trastuzumab is so-called antibody-dependent cell-mediated phagocytosis (ADCP) or cytotoxicity (ADCC). This is a defensive reaction (destruction) of the endogenous immune system against cancer cells.

Histone deacetylase inhibitors make cancer cells easier to be attack
The "packing density" of a cell's DNA is largely regulated via so-called histones (protein molecules, on which the DNA winds itself like on a spool). By modifying these histones, so-called "histone modification", it is possible to loosen the "packing density". The "loosening" of the DNA is regulated by an acetylation (replacement of one hydrogen atom by an acetyl group) of the histones. This process is mediated by histone acetyl transferases (HAT). As a consequence, the DNA is easier to "read" and, in turn, this can lead to amore rapid tumor growth and tumor spread. So-called histone deacetylases (HDACs) are the antagonists of HAT and they can increase the "packing density" of the DNA again, making it more difficult to "read". Histone deacetylase inhibitors (HDACi), such as valproic acid (drug from the group of antiepileptics) and vorinostat are currently being successfully trialled or used for a number of different cancers. However, the influence of HDACi on trastuzumab-mediated ADCP (antibody-dependent cell-mediated phagocytosis) has not yet been investigated.

Scientists from the Comprehensive Cancer Center (CCC) of MedUni Vienna and Vienna General Hospital – including the Department of Pathology as well as the Division of General Surgery of the Department of Surgery – have now shown that the HDACi valproic acid and vorinostat can enhance trastuzumab-mediated ADCP. Mechanistically, the cancer cells are made easier to attack and are less resistant to "phagocytosing cells" of the immune system. "It is also easier for the phagocytes to bind to the antibody trastuzumab and hence to find the tumor," explains lead author Johannes Längle from the Division of General Surgery of the Department of Surgery and member of the CCC.

Support for the endogenous immune system
Principal investigator, Michael Bergmann (Division of General Surgery within the Department of Surgery and member of the CCC) sees in the study a key role of the immune system in the mechanism of HDACi-enhanced, trastuzumab-mediated ADCP. He says: "Enhanced trastuzumab-mediated phagocytosis is the result of the multimodal HDACi treatment effect. The immunomodulatory effects of these HDACi can also offer a rational combined treatment approach for other antibody therapies and other types of cancer entities. However, a few more detailed studies are still required to confirm this."

Service: Journal for ImmunoTherapy of Cancer
Laengle J, Kabiljo J, Hunter L, Homola J, Prodinger S, Egger G, Bergmann M. Histone deacetylase inhibitors valproic acid and vorinostat enhance trastuzumab-mediated antibody-dependent cell-mediated phagocytosis. J Immunother Cancer 2020. 8:e000195. doi:10.1136/jitc-2019-000195
Available at: doi.org/10.1136/jitc-2019-000195