Immune modulation underpins the anti-cancer activity of HDAC inhibitors
Wiktoria Blaszczak1, Geng Liu2, Hong Zhu2,3
1Celleron Therapeutics Ltd, Oxford, UK.
Abstract:
Aberrant protein acetylation is strongly linked to tumorigenesis, and modulating acetylation through targeting histone deacetylase (HDAC) with small-molecule inhibitors has been the focus of clinical trials. However, clinical success on solid tumours, such as colorectal cancer (CRC), has been limited, in part because the cancer-relevant mechanisms through which HDAC inhibitors act remain largely unknown. Here, we have explored, at the genome-wide expression level, the effects of a novel HDAC inhibitor CXD101. In human CRC cell lines, a diverse set of differentially expressed genes were up- and downregulated upon CXD101 treatment. Functional profiling of the expression data highlighted immune-relevant concepts related to antigen processing and natural killer cell-mediated cytotoxicity. Similar profiles were apparent when gene expression was investigated in murine colon26 CRC cells treated with CXD101. Significantly, these changes were also apparent in syngeneic colon26 tumours growing in vivo. The ability of CXD101 to affect immune-relevant gene expression coincided with changes in the tumour microenvironment (TME), especially in the subgroups of CD4 and CD8 tumour-infiltrating T lymphocytes. The altered TME reflected enhanced antitumour activity when CXD101 was combined with immune checkpoint inhibitors (ICIs), such as anti-PD-1 and anti-CTLA4. The ability of CXD101 to reinstate immune-relevant gene expression in the TME and act together with ICIs provides a powerful rationale for exploring the combination therapy in human cancers.
Insights
A novel histone deacetylase (HDAC) inhibitor, CXD101, alters gene expression in colorectal cancer (CRC) cells and tumors, enhancing immune responses. This suggests CXD101 combined with immune checkpoint inhibitors (ICIs) could improve cancer therapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Aberrant protein acetylation is linked to cancer, with histone deacetylase (HDAC) inhibitors showing limited clinical success in solid tumors like colorectal cancer (CRC).
- The precise mechanisms of HDAC inhibitors in cancer remain largely unknown, hindering their therapeutic application.
Purpose of the Study:
- To investigate the genome-wide expression effects of a novel HDAC inhibitor, CXD101, in colorectal cancer.
- To explore the impact of CXD101 on the tumor microenvironment (TME) and its potential synergy with immune checkpoint inhibitors (ICIs).
Main Methods:
- Genome-wide gene expression analysis of human CRC cell lines and murine colon26 CRC cells treated with CXD101.
- Analysis of tumor microenvironment changes, including CD4 and CD8 T lymphocyte infiltration.
- Assessment of CXD101 efficacy in combination with anti-PD-1 and anti-CTLA4 immune checkpoint inhibitors.
Main Results:
- CXD101 treatment induced diverse gene expression changes in CRC cells, including immune-relevant pathways like antigen processing and natural killer cell-mediated cytotoxicity.
- Similar immune-related gene expression profiles were observed in murine CRC cells and tumors in vivo.
- CXD101 altered the tumor microenvironment, increasing CD4 and CD8 T lymphocyte infiltration, and enhanced anti-tumor activity when combined with ICIs.
Conclusions:
- CXD101 effectively modulates immune-relevant gene expression in colorectal cancer.
- The combination of CXD101 with ICIs demonstrates enhanced anti-tumor activity, suggesting a promising therapeutic strategy for human cancers.
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