Protein acetylation plays a key role in regulating cellular processes and is subject to aberrant control in diverse pathologies. Although histone deacetylase (HDAC) inhibitors are approved drugs for certain cancers, it is not known whether they can be deployed in other therapeutic contexts. We have explored the clinical HDAC inhibitor, zabadinostat/CXD101, and found that it is a stand-alone regulator of the adaptive immune response. Zabadinostat treatment increased expression of MHC class I and II genes in a variety of cells, including dendritic cells (DCs) and healthy tissue. Remarkably, zabadinostat enhanced the activity of DCs, and CD4 and CD8 T lymphocytes. Using an antigenic peptide presented to the immune system by MHC class I, zabadinostat caused an increase in antigen-specific CD8 T lymphocytes. Further, mice immunised with covid19 spike protein and treated with zabadinostat exhibit enhanced covid19 neutralising antibodies and an increased level of T lymphocytes. The enhanced humoral response reflected increased activity of T follicular helper (Tfh) cells and germinal centre (GC) B cells. Our results argue strongly that zabadinostat has potential to augment diverse therapeutic agents that act through the immune system.
© 2023. The Author(s).

Pancreatic cancer stem-like cells (P-CSLCs) are thought to be associated with poor prognosis. Previously, we used proteomic analysis to identify a chaperone pro-phagocytic protein calreticulin (CALR) as a P-CSLC-specific protein. This study aimed to investigate the association between CALR and P-CSLC.
PANC-1-Lm cells were obtained as P-CSLCs from a human pancreatic cancer cell line, PANC-1, using a sphere induction medium followed by long-term cultivation on laminin. To examine the cancer stem cell properties, subcutaneous injection of the cells into immune-deficient mice and sphere formation assay were performed. Cell surface expression analysis was performed using flow cytometry.
PANC-1-Lm showed an increased proportion of cell surface CALR-positive and side-population fractions compared with parental cells. PANC-1-Lm cells also had higher frequency of xenograft tumor growth and sphere formation than PANC-1 cells. Moreover, sorted CALRhigh cells from PANC-1-Lm had the highest sphere formation frequency among tested cells. Interestingly, the number of programmed death-ligand 1-positive cells among CALRhigh cells was increased as well, whereas that of human leukocyte antigen class I-positive cells decreased.
In addition to the cancer stem cell properties, the P-CSLC, which showed elevated CALR expression on the cell surface, might be associated with evasion of immune surveillance.
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.