NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors

Macfarlane, Alexander W.; Jillab, Mowafaq; Smith, Mitchell R.; Alpaugh, R. Katherine; Cole, Marion E.; Litwin, Samuel; Millenson, Michael; Al‐Saleem, Tahseen; Cohen, Adam D.; Campbell, Kerry S.

doi:10.1080/2162402x.2017.1330235

Cited by 51 publications

(65 citation statements)

References 66 publications

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“…Functional and phenotypic impairments of NK cells have been reported in a variety of solid and hematologic malignancies, including CLL [10, 35]. Dysregulation and imbalance of activating and inhibitory NK cell receptors could be one of the main reasons for NK cell impairment in CLL [36]. The results from the present study revealed that NK cells of CLL patients express higher levels of Tim-3 and lower levels of NKp30 in comparison to those of healthy individuals.…”

Section: Discussionsupporting

confidence: 62%

Dysregulated Expression of Tim-3 and NKp30 Receptors on NK Cells of Patients with Chronic Lymphocytic Leukemia

et al. 2019

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Background: In this study, the expression pattern of NKp30 and T cell immunoglobulin and mucin domain-containing molecule-3 (Tim-3), as candidates for activating and inhibitory receptors of NK cells, were evaluated in patients with chronic lymphocytic leukemia (CLL). Patients and Methods: 24 CLL patients and 19 healthy controls were enrolled. Fresh peripheral blood was collected from all subjects and stained with fluorochrome-conjugated antibodies. The frequency of CD56+/CD3–/NKp30+ and CD56+/CD3–/Tim-3+ cells was determined by multicolor flow cytometry. Results: Our results revealed that Tim-3 is significantly upregulated on natural killer (NK) cells of CLL patients in comparison to healthy controls. NK cells of CLL patients showed lower expression of NKp30-activating receptor compared to controls. Tim-3 expression pattern on NK cells of CLL patients was correlated with poor prognostic factors including low hemoglobin level, high absolute lymphocyte count, and high serum C-reactive protein level. Conclusion: Dysregulated expression of Tim-3 and NKp30 receptors confirms the exhaustion state of NK cells in CLL. Our data introduce Tim-3 as a promising biomarker and potential target for immunotherapy of CLL.

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Section: Discussionsupporting

confidence: 62%

Dysregulated Expression of Tim-3 and NKp30 Receptors on NK Cells of Patients with Chronic Lymphocytic Leukemia

et al. 2019

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“…In contrast to CD8 1 T cells, NK cell cytokine production and degranulation are impaired in untreated CLL patients. 17,18 Following venetoclax-obinutuzumab treatment, degranulation, as well as IFN-g production, of NK cells improved significantly ( Figure 4G).…”

Section: Tumor-supportive T-cell Subsets Decline During Venetoclax-obmentioning

confidence: 98%

“…[13][14][15][16] NK cell functionality is also impaired in CLL, particularly with regard to degranulation and cytotoxicity. 17,18 Similar to other B-cell lymphomas, such as follicular lymphoma, the lymph node (LN) microenvironment in CLL is thought to be the predominant site of interaction between the malignant cells and tumor-associated and tumor-specific immune cells. 19 However, data on immune abnormalities in CLL patients are primarily obtained from peripheral blood (PB) studies, and little is known about the composition of nonmalignant lymphocytes in LN tissue or how this relates to PB.…”

Section: Introductionmentioning

confidence: 99%

Distinct immune composition in lymph node and peripheral blood of CLL patients is reshaped during venetoclax treatment

et al. 2019

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Morbidity and mortality due to immunosuppression remain among the foremost clinical challenges in chronic lymphocytic leukemia (CLL). Although immunosuppression is considered to originate within the lymph node (LN) microenvironment, alterations in T and natural killer (NK) cells have almost exclusively been studied in peripheral blood (PB). Whereas chemoimmunotherapy further deteriorates immune function, novel targeted agents like the B-cell lymphoma 2 inhibitor venetoclax potentially spare nonmalignant lymphocytes; however, the effects of venetoclax on nonleukemic cells have not been explored. We address these unresolved issues using a comprehensive analysis of nonmalignant lymphocytes in paired LN and PB samples from untreated CLL patients, and by analyzing the effects of venetoclax-based treatment regimens on the immune system in PB samples from previously untreated and relapsed/refractory patients. CLL-derived LNs contained twice the amount of suppressive regulatory T cells (Tregs) and CLL supportive follicular T helper (Tfh) cells compared with PB. This was accompanied by a low frequency of cytotoxic lymphocytes. The expression of PD-1 by CD8+ T cells was significantly higher in LN compared with PB. Venetoclax-based treatment led to deep responses in the majority of patients, but also to decreased absolute numbers of B, T, and NK cells. Tfh cell, Treg, and PD-1+ CD8+ T cell numbers were reduced more than fivefold after venetoclax-based therapy, and overproduction of inflammatory cytokines was reduced. Furthermore, we observed restoration of NK cell function. These data support the notion that the immunosuppressive state in CLL is more prominent within the LN. Venetoclax-based regimens reduced the immunosuppressive footprint of CLL, suggesting immune recovery after the elimination of leukemic cells.

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“…TriKE 161519 was recently described by Felices et al (271) for treatment of chronic lymphocytic leukemia (CLL); this antibody consists of anti-CD19 and anti-CD16 fragments, with an additional IL-15 moiety. Inclusion of the IL-15 moiety may be beneficial in CLL patients, who display low numbers and survival of mature and functional NK cells (272). TriKE 161519 induced superior NK cell activity against lymphoma cell lines and primary CLL patient cells compared to Rituximab, and, importantly, promoted NK cell survival and proliferation.…”

Section: Engagers Of Nk Cells To Unleash Nk Cell Activitymentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors

Cited by 51 publications

References 66 publications

Dysregulated Expression of Tim-3 and NKp30 Receptors on NK Cells of Patients with Chronic Lymphocytic Leukemia

Dysregulated Expression of Tim-3 and NKp30 Receptors on NK Cells of Patients with Chronic Lymphocytic Leukemia

Distinct immune composition in lymph node and peripheral blood of CLL patients is reshaped during venetoclax treatment

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

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