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HDAC6 Inhibition Alleviates CLL-Induced T-Cell Dysfunction and Enhances Immune Checkpoint Blockade Efficacy in the E?-TCL1 Model.

ABSTRACT: Development of chronic lymphocytic leukemia (CLL) is associated with severe immune dysfunction. T-cell exhaustion, immune checkpoint upregulation, and increase of regulatory T cells contribute to an immunosuppressive tumor microenvironment. As a result, CLL patients are severely susceptible to infectious complications that increase morbidity and mortality. CLL B-cell survival is highly dependent upon interaction with the supportive tumor microenvironment. It has been postulated that the reversal of T-cell dysfunction in CLL may be beneficial to reduce tumor burden. Previous studies have also highlighted roles for histone deacetylase 6 (HDAC6) in regulation of immune cell phenotype and function. Here, we report for the first time that HDAC6 inhibition exerts beneficial immunomodulatory effects on CLL B cells and alleviates CLL-induced immunosuppression of CLL T cells. In the E?-TCL1 adoptive transfer murine model, genetic silencing or inhibition of HDAC6 reduced surface expression of programmed death-ligand 1 (PD-L1) on CLL B cells and lowered interleukin-10 (IL-10) levels. This occurred concurrently with a bolstered T-cell phenotype, demonstrated by alteration of coinhibitory molecules and activation status. Analysis of mice with similar tumor burden indicated that the majority of T-cell changes elicited by silencing or inhibition of HDAC6 in vivo are likely secondary to decrease of tumor burden and immunomodulation of CLL B cells. The data reported here suggest that CLL B cell phenotype may be altered by HDAC6-mediated hyperacetylation of the chaperone heat shock protein 90 (HSP90) and subsequent inhibition of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Based on the beneficial immunomodulatory activity of HDAC6 inhibition, we rationalized that HDAC6 inhibitors could enhance immune checkpoint blockade in CLL. Conclusively, combination treatment with ACY738 augmented the antitumor efficacy of anti-PD-1 and anti-PD-L1 monoclonal antibodies in the E?-TCL1 adoptive transfer murine model. These combinatorial antitumor effects coincided with an increased cytotoxic CD8⁺ T-cell phenotype. Taken together, these data highlight a role for HDAC inhibitors in combination with immunotherapy and provides the rationale to investigate HDAC6 inhibition together with immune checkpoint blockade for treatment of CLL patients.

SUBMITTER: Maharaj K

PROVIDER: S-EPMC7719839 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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HDAC6 Inhibition Alleviates CLL-Induced T-Cell Dysfunction and Enhances Immune Checkpoint Blockade Efficacy in the Eμ-TCL1 Model.

Maharaj Kamira K Powers John J JJ Mediavilla-Varela Melanie M Achille Alex A Gamal Wael W Quayle Steven S Jones Simon S SS Sahakian Eva E Pinilla-Ibarz Javier J

Frontiers in immunology 20201123

Development of chronic lymphocytic leukemia (CLL) is associated with severe immune dysfunction. T-cell exhaustion, immune checkpoint upregulation, and increase of regulatory T cells contribute to an immunosuppressive tumor microenvironment. As a result, CLL patients are severely susceptible to infectious complications that increase morbidity and mortality. CLL B-cell survival is highly dependent upon interaction with the supportive tumor microenvironment. It has been postulated that the reversal ...[more]

PMID: 33329575

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Project description:Background: Colorectal cancer (CRC) is the third most common malignancy worldwide. The presence of CD8 tumor-infiltrating T lymphocytes (TILs) is associated with improved prognosis and therapeutic response in CRC patients. FOLFOX chemotherapy is a standard first-line treatment for patients with CRC. Yet, the effect of FOLFOX on TILs is poorly understood. Specifically, it is unclear whether FOLFOX therapy impacts the phenotype and functionality of tumor antigen specific TILs. Immune checkpoint blockade (ICB) has significantly improved clinical outcome of cancer treatment but has shown limited efficacy in CRC patients. Recently, ICB efficiency has been linked to reinvigoration of T cells with a non-terminally dysfunctional phenotype. Here, we investigate the effect of FOLFOX on CD8 T cell tumor accumulation, phenotype and function and tested the combination of FOLFOX and ICB to improve tumor regression. Methods: A mouse model of CRC expressing a human tumor antigen was used to study the effect of FOLFOX on tumor growth and TILs phenotype and function. Tetramers were used to identify and monitor phenotype and function of tumor specific TILs. The phenotype and function of TILs were compared between FOLFOX and control treatment through flow cytometry, in vivo depletion and ex vivo stimulation. Furthermore, the anti-tumor effect of the single drug or combined therapy with anti-PD1 were also assessed. Results: We show that FOLFOX treatment effectively controlled tumor burden and this was dependent on CD8 T cells. FOLFOX enabled TILs to remain in a functional differentiation state characterized by lower levels of inhibitory receptors PD-1 and TIM-3 and a CD38loCD101loTIM-3-TCF-1hi phenotype. Consistent with this, TILs from FOLFOX treated tumors exhibited higher effector function. Importantly, while anti-PD-1 treatment alone had no significant effect on tumor burden, FOLFOX and PD-1 checkpoint blockade combination showed significant tumor control. Conclusions: FOLFOX treatment impacts the phenotype and function of TILs making them more responsive to checkpoint blockade. This study highlights the importance of combining chemotherapy and ICB to optimize treatment efficacy in patients with colorectal cancer.

Project description:OBJECTIVE:Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC). DESIGN:Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific CCRK-inducible transgenic (TG) mice and Hepa1-6 orthotopic HCC models using CRISPR/Cas9-mediated Ccrk depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy. RESULTS:Tumour-infiltrating CD11b+CD33+HLA-DR- MDSCs from patients with HCC potently inhibited autologous CD8+T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b+CD33+HLA-DR- MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-?B (NF-?B) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-?B-EZH2 co-binding to IL-6 promoter. Hepatic CCRK induction in TG mice activated the EZH2/NF-?B/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous Ccrk or hepatic IL-6 increased interferon ?+tumour necrosis factor-?+CD8+ T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous Ccrk depletion upregulated PD-L1 expression and increased intratumorous CD8+ T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC. CONCLUSION:Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.

Dataset Information

HDAC6 Inhibition Alleviates CLL-Induced T-Cell Dysfunction and Enhances Immune Checkpoint Blockade Efficacy in the E?-TCL1 Model.

Publications

HDAC6 Inhibition Alleviates CLL-Induced T-Cell Dysfunction and Enhances Immune Checkpoint Blockade Efficacy in the Eμ-TCL1 Model.

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