Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia

Maharaj, Kamira; Sahakian, Eva; Pinilla‐Ibarz, Javier

doi:10.1182/bloodadvances.2017006809

Cited by 18 publications

(17 citation statements)

References 95 publications

(91 reference statements)

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“… 11 Besides its direct cytotoxic activity against malignant B cells, ibrutinib also exerts immunomodulatory effects (reviewed by Maharaj et al .). 12 Ibrutinib-mediated inhibition of STAT3 results in decreased expression of immunosuppressive molecules, such as PD-L1 and IL-10, by CLL cells. 13 Gunderson et al .…”

Section: Introductionmentioning

confidence: 99%

Combining ibrutinib and checkpoint blockade improves CD8+ T-cell function and control of chronic lymphocytic leukemia in Em-TCL1 mice

et al. 2020

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Ibrutinib is a bruton’s tyrosine kinase (BTK) inhibitor approved for the treatment of multiple B-cell malignancies, including chronic lymphocytic leukemia (CLL). In addition to blocking B-cell receptor signaling and chemokine receptor-mediated pathways in CLL cells, that are known drivers of disease, ibrutinib also affects the microenvironment in CLL via targeting BTK in myeloid cells and IL-2–inducible T-cell kinase (ITK) in T-cells. These non-BTK effects were suggested to contribute to the success of ibrutinib in CLL. By using the Eµ-TCL1 adoptive transfer mouse model of CLL, we observed that ibrutinib effectively controls leukemia development, but also results in significantly lower numbers of CD8+ effector T-cells, with lower expression of activation markers, as well as impaired proliferation and effector function. Using CD8+ T-cells from a T-cell receptor (TCR) reporter mouse, we verified that this is due to a direct effect of ibrutinib on TCR activity, and demonstrate that co-stimulation via CD28 overcomes these effects. Most interestingly, combination of ibrutinib with blocking antibodies targeting PD-1/PD-L1 axis in vivo improved CD8+ T-cell effector function and control of CLL. In sum, these data emphasize the strong immunomodulatory effects of ibrutinib and the therapeutic potential of its combination with immune checkpoint blockade in CLL.

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Section: Introductionmentioning

confidence: 99%

Combining ibrutinib and checkpoint blockade improves CD8+ T-cell function and control of chronic lymphocytic leukemia in Em-TCL1 mice

et al. 2020

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“…cytotoxic potential. Quantification of these populations based on xshift analysis demonstrated that some clusters with cytotoxic potential (6,9,10,11,12) appeared enriched in treatment groups ( Figure S5B). The expression distribution of each marker in the tSNE plot is shown in Figure S6.…”

Section: Combination Of Hdac6 Inhibition and Pd-1/pd-l1 Blockade Augmmentioning

confidence: 99%

“…Based on these observations, it has been postulated that reversal of T-cell dysfunction may restore Tcell mediated antitumor activity. Detailed reviews of CLL T-cell dysfunction can be found here (6,7).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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 Eμ-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 Eμ-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.

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“…Furthermore, ibrutinib treatment leads to an immediate downregulation of a plethora of chemokines in the plasma, mainly through alteration of CLL cells and TME cells in the lymph nodes [157]. The immunomodulatory effects of BCR signaling inhibitors has recently been reviewed by Maharaj et al [158]. Interestingly, IL-4 expression increases surface IgM expression and reduces CXCR4 and CXCR5 and seems to render CLL cells resistant to BCR-signaling inhibitors ibrutinib and idelalisib [159].…”

Section: Immune Cells In the Tumor Microenvironmentmentioning

confidence: 99%

Targeting the Immune Microenvironment in Lymphomas of B-Cell Origin: From Biology to Clinical Application

Mulder

Wahlin

Österborg

et al. 2019

Cancers

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In lymphomas of B-cell origin, cancer cells orchestrate an inflammatory microenvironment of immune and stromal cells that sustain the tumor cell survival and growth, known as a tumor microenvironment (TME). The features of the TME differ between the different lymphoma types, ranging from extremely inflammatory, such as in Hodgkin lymphoma, to anergic, leading to immune deficiency and susceptibility to infections, such as in chronic lymphocytic leukemia. Understanding the characteristic features of the TME as well as the interactions between cancer and TME cells has given insight into the pathogenesis of most lymphomas and contributed to identify novel therapeutic targets. Here, we summarize the preclinical data that contributed to clarifying the role of the immune cells in the TME of different types of lymphomas of B-cell origin, and explain how the understanding of the biological background has led to new clinical applications. Moreover, we provide an overview of the clinical results of trials that assessed the safety and efficacy of drugs directly targeting TME immune cells in lymphoma patients.

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Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia

Cited by 18 publications

References 95 publications

Combining ibrutinib and checkpoint blockade improves CD8+ T-cell function and control of chronic lymphocytic leukemia in Em-TCL1 mice

Combining ibrutinib and checkpoint blockade improves CD8+ T-cell function and control of chronic lymphocytic leukemia in Em-TCL1 mice

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

Targeting the Immune Microenvironment in Lymphomas of B-Cell Origin: From Biology to Clinical Application

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