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Immune modulation underpins the anti-cancer activity of HDAC inhibitors

ABSTRACT: We have explored at the genome-wide expression level the effects of the novel HDAC inhibitor CXD101. In human CRC cell lines, a diverse set of differentially expressed genes were up- and down-regulated. Functional profiling of the expression data highlighted immune-relevant concepts related to antigen processing and natural killer (NK) cell mediated cytotoxicity. Similar gene profiles were apparent when global gene expression was investigated in murine CT26 cells treated with CXD101, which were also apparent in syngeneic CT26 tumours growing in vivo. The ability of CXD101 to affect immune-relevant gene expression coincided with changes in the tumour micro-environment (TME), especially in the sub-groups of tumour-infiltrating lymphocytes which occurred upon CXD101 treatment. The altered TME reflected synergistic anti-tumour activity apparent when CXD101 was combined with immune oncology (IO) agents, like anti-PD1 and anti-CTLA4.The ability of CXD101 to instate antigen presentation and augment NK activity in the TME, combined with the synergy between HDAC inhibitors and IO agents, provides a powerful rationale for exploring the combination effect in human cancers.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE158164 | GEO | 2021/06/30

REPOSITORIES: GEO

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Project description:Cervical cancer (CC) is one of the most common malignancy in women worldwide. It is characterized by a natural continuous phenomenon, that is, it is in the initial stage of HPV infection, progresses to intraepithelial neoplasia, and then develops into invasion and metastasis. Determining the complexity of tumor microenvironment (TME) can deepen our understanding of lesion progression and provide novel therapeutic strategies for CC. We performed the single-cell RNA sequencing on the normal cervix, intraepithelial neoplasia, primary tumor and metastatic lymph node tissues to describe the composition, lineage, and functional status of immune cells and mesenchymal cells at different stages of CC progression. A total of 59913 single cells were obtained and divided into 9 cellular clusters, including immune cells (T/NK cells, macrophages, B cells, plasma cells, mast cells and neutrophils) and mesenchymal cells (endothelial cells, smooth muscle cells and fibroblasts). Our results showed that there were distinct cell subpopulations in different stages of CC. High-stage intraepithelial neoplasia (HSIL) tissue exhibited a low, recently activated TME, and it was characterized by high infiltration of tissue-resident CD8 T cell, effector NK cells, Treg, DC1, pDC, and M1-like macrophages. Tumor tissue displayed high enrichment of exhausted CD8 T cells, resident NK cells and M2-like macrophages, suggesting immunosuppressive TME. Metastatic lymph node consisted of naive T cell, central memory T cell, circling NK cells, cytotoxic CD8+ T cells and effector memory CD8 T cells, suggesting an early activated phase of immune response. This study is the first to delineate the transcriptome profile of immune cells during CC progression using single-cell RNA sequencing. Our results indicated that HSIL exhibited a low, recently activated TME, tumor displayed immunosuppressive statue, and metastatic lymph node showed early activated phase of immune response. Our study enhanced the understanding of dynamic change of TME during CC progression and has implications for the development of novel treatments to inhibit the initiation and progression of CC.

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Immune modulation underpins the anti-cancer activity of HDAC inhibitors

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