Abstract
Immune checkpoint inhibitors (ICIs) have shown clinical benefit in solid tumors, with modest rates of clinical response. Hence, improved therapeutic approaches need to be investigated. Herein, we assessed a combination of chidamide plus celecoxib (called CC-01) combined with programmed cell death protein 1 (PD-1) blockade in a CT26 model as potent tumor microenvironment (TME) regulator. The antitumor activity was assessed by measuring tumor size, overall response rate, and survival rate. Immune profiling of tumor-infiltrating lymphocytes was performed by flow cytometry. Tumor tissues were assessed by chip assay to predict the possible pathway. Tumor size was significantly reduced in mice treated with CC-01 combined with or without anti-PD-1 antibody, however the triple combination therapy consistently demonstrated that it significantly increased both the ORR and survival rate in term of clinical applications. In the combination group, immune landscape profiling revealed decreased populations of immunosuppressive regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Analysis of the mouse tumor chip data using Gene Ontology enrichment analysis of biological processes revealed that the triple combination upregulated genes associated with responses to interferon-gamma. Our results demonstrated that CC-01 possessed potent TME regulatory properties, augmenting the antitumor effect when combined with ICIs. This antitumor effect was achieved by altering the immune landscape in TILs (tumor-infiltrating lymphocytes) and was associated with immune cell activation in the TME. Furthermore, CC-01 demonstrated potent anticancer immune response activity, mainly reducing the number and function of several immunosuppressive cells. The combination of CC-01 with an ICI will further enhance the anticancer effect and boost the immune response rate. Collectively, our results support the clinical evaluation of CC-01 in combination with ICIs in several advanced cancers.
Highlights
Abbreviations COX2 Cyclooxygenase 2 cytotoxic T-lymphocyte (CTL) Cytotoxic T-lymphocyte DC Dendritic cells EM Effector memory Gzm Granzyme histone deacetylase (HDAC) Histone deacetylase HDACi HDAC inhibitor IFN-γ Interferon-gamma i.p
The combination of anti-progression disease (PD)-1 antibody with entinostat resulted in significant suppression of tumor growth, but no eradication of primary tumors in 7 mice, extending survival to 70% at day 42 after tumor implantation when compared with anti-PD-1 antibody (SFig. 1C,D)
Our findings showed no significant changes in circulating lymphocytes and granulocytes; monocytes were significantly reduced by approximately 22% after chidamide + celecoxib treatment and 25% after chidamide + celecoxib + anti-PD-1 antibody (Fig. 5A–C, SFig. 6A)
Summary
Abbreviations COX2 Cyclooxygenase 2 CTL Cytotoxic T-lymphocyte DC Dendritic cells EM Effector memory Gzm Granzyme HDAC Histone deacetylase HDACi HDAC inhibitor IFN-γ Interferon-gamma i.p. Preclinical studies have revealed that histone deacetylase (HDAC) inhibitors modulate the activation state of the APCs to effectively prime naive Ag-specific C D4+ T cells and restore the responsiveness of tolerant T cells isolated from tumor-bearing m ice[15]. Chidamide selectively inhibits the activity of HDACs 1, 2, 3, and 10, demonstrating its anticancer functions as a genuine epigenetic modulator via the following mechanisms: induction of growth arrest and apoptosis in the blood and lymphoid-derived tumor cells; the reversal of epithelial-mesenchymal transitions and drug resistance in tumor cells; importantly, enhancement of natural killer (NK)-cell and antigen-specific C D8+ cytotoxic T-lymphocyte (CTL) mediated cellular antitumor immunity[18,19,20,21,22]. Prostaglandin E2 (PGE2) is a critical product of cyclooxygenase 2 (COX-2), which is overexpressed in most human cancers, affects tumor progression and immunosuppression, and stimulates arginase-1 (ARG-1) and nitric oxide synthase (NOS)-2 secretion from
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
