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A heatmap visualizing the relationship of KIR genes and therapy responses in CML patients treated with dasatinib as first-line therapy. ( A ) The patients were split into two groups by an unsupervised segregative clustering method using the profiles of all the KIR genes screened. The red color stands for the absence and the white for the presence of a specific KIR gene. ( B ) Therapy response is shown on logarithmic scale showing the amount of BCR-ABL1 transcript found in the blood 12 months after start of dasatinib therapy.
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Tyrosine kinase inhibitors have greatly improved the prognosis of chronic myeloid leukemia (CML). In addition to direct kinase inhibition, their effects can also be mediated through immune modulation, such as expansion of cytotoxic T and natural-killer cells observed during dasatinib therapy. As natural-killer cell and partially CD8(+) T-cell funct...
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Context 1
... We hypothesized that KIR genes could have a combinatorial effect and therefore we next analyzed whether the KIR gene profile can segregate patients based on the therapy response. First-line dasatinib patients were clustered into two groups by the KIR gene profiles and the BCR-ABL1 transcript levels were compared between the groups by t test (Fig. 2A). The two groups of patients that emerged by unsupervised segre- gative clustering analysis ( Fig. 2A) showed significant differ- ences in the BCR-ABL1 transcript levels at 12 months (p 5 0.047; Fig. 2B). Interestingly, group 1, including patients with the better molecular response, was characterized by the absence of several inhibiting ...
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... the KIR gene profile can segregate patients based on the therapy response. First-line dasatinib patients were clustered into two groups by the KIR gene profiles and the BCR-ABL1 transcript levels were compared between the groups by t test (Fig. 2A). The two groups of patients that emerged by unsupervised segre- gative clustering analysis ( Fig. 2A) showed significant differ- ences in the BCR-ABL1 transcript levels at 12 months (p 5 0.047; Fig. 2B). Interestingly, group 1, including patients with the better molecular response, was characterized by the absence of several inhibiting (2DL5A and 2DL5B) and activating KIR genes (2DS2 and 2DS1). In contrast, patients in group 2, with a ...
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... patients were clustered into two groups by the KIR gene profiles and the BCR-ABL1 transcript levels were compared between the groups by t test (Fig. 2A). The two groups of patients that emerged by unsupervised segre- gative clustering analysis ( Fig. 2A) showed significant differ- ences in the BCR-ABL1 transcript levels at 12 months (p 5 0.047; Fig. 2B). Interestingly, group 1, including patients with the better molecular response, was characterized by the absence of several inhibiting (2DL5A and 2DL5B) and activating KIR genes (2DS2 and 2DS1). In contrast, patients in group 2, with a worse molecular responses, in general had a higher frequency of all KIRs ( Fig. ...
Context 4
... at 12 months (p 5 0.047; Fig. 2B). Interestingly, group 1, including patients with the better molecular response, was characterized by the absence of several inhibiting (2DL5A and 2DL5B) and activating KIR genes (2DS2 and 2DS1). In contrast, patients in group 2, with a worse molecular responses, in general had a higher frequency of all KIRs ( Fig. ...
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Background:
Natural Killer (NK) cells are innate lymphoid cells that can be cytotoxic toward a large panel of solid tumors and hematological malignancies including chronic myeloid leukemia (CML). Such a cytotoxicity depends on various receptors. Killer immunoglobulin-like receptors (KIR) belong to these receptors and are involved in maturation pro...
Natural killer (NK) cells assume graft-versus-leukemia alloreactivity after hematopoietic stem-cell transplantation (HSCT) through their inhibitory killer cell immunoglobulin-like receptors (KIRs). KIR2D family members recognize human leukocyte antigen (HLA)-C alleles with Asn80 (HLA-C1) or Lys80 (HLA-C2). The predominance of HLA-C1 over HLA-C2 and...
Citations
... As for constitutional genetics, a specific HMGCLL1 haplotype and polymorphic variation at BIM, ASXL1 and killer immunoglobulin-like receptor (KIR) loci have all been associated with response to TKI therapy or outcome after treatment cessation [58][59][60][61][62][63] but in the absence of clear clinical actionability and systematic validation, none are yet incorporated into routine risk stratification. ...
From the laboratory perspective, effective management of patients with chronic myeloid leukemia (CML) requires accurate diagnosis, assessment of prognostic markers, sequential assessment of levels of residual disease and investigation of possible reasons for resistance, relapse or progression. Our scientific and clinical knowledge underpinning these requirements continues to evolve, as do laboratory methods and technologies. The European LeukemiaNet convened an expert panel to critically consider the current status of genetic laboratory approaches to help diagnose and manage CML patients. Our recommendations focus on current best practice and highlight the strengths and pitfalls of commonly used laboratory tests.
... CML patients treated with dasatinib presented more classical NK cells (CD3 − CD56 + ) and matured NK cells (CD56 + CD57 + ) compared to imatinib-or nilotinib-treated patients [38]. These patients also presented lower expression of NK-inhibitory markers (KIR2DL5A, KIR2DL5B and KIR2DL5), which was associated with an MMR [39] and an increase in KIR2DL1 expression [8]. ...
... Consequently, dasatinib could be useful, especially in the patients that do not have these protective features, to enhance cytotoxic activity of NK cells against CML cells by increasing memorylike NKG2C + CD57 + NK cells [70], γδ T cells and other innate CD8 + T cells [7,30,37,44]. In addition, these innate cells could express high levels of the activation receptor NKG2C, NKG2D, NKp46 or DNAM-1 and downregulate some inhibitory receptors such as NKG2A and KIR2DL5 [7,39,41,44] (Figure 1A). ...
... (p = 0,0489, p = 0,030 и p = 0,0272 соответственно). Кроме того, выявлена тенденция к улучшению МО на терапию дазатинибом при отсутствии у пациента активирующих генов KIR2DS1 (p = 0,061) и KIR2DS2 (p = 0,071) [29]. К настоящему времени неизвестно, почему отсутствие активирующих KIR, которые должны стимулировать функцию NK-клеток, может быть связано с улучшением МО на терапию ИТК. ...
The development of tyrosine kinase inhibitors (TKIs) and their introduction into clinical practice considerably improved the prognosis for chronic myeloid leukemia (CML) patients. About 50 % of patients with achieved deep molecular response are eligible for safe TKI discontinuation. Despite these advances, no reliable biomarkers are known to predict a response and sustaining treatment-free remission after TKI withdrawal. As TKIs do not destroy leukemic stem cells, which can be responsible for relapse, critical importance in CML is attached to natural killers (NK-cells) having antitumor activity. Functional activity of NK-cells is evaluated by expression level and repertoire of killer cell immunoglobulin-like receptors (KIR). Current studies demonstrate that a patient’s KIR genotype affects the probability of achieving early and deep molecular responses to first- and second-generation TKIs, progression-free and overall survivals, and sustaining treatment-free remission. On that ground, KIR-genetic factors can be regarded as promising predictors of response to TKI therapy in CML. Early clinical studies, which dealt with monoclonal antibodies blocking the inhibitory KIR in order to increase NK-cell activity, revealed an acceptable safety profile and efficacy in some hematological diseases (such as acute myeloid leukemia, multiple myeloma, Т-cell lymphoma) if used in combination with cytostatic drugs or antitumor monoclonal antibodies. KIR genotype determination can contribute to the development of effective therapies of this malignant hematological tumor.
... Nonetheless, these studies have produced heterogeneous results and have not analyzed the other KIR ligands, HLA-G and HLA-F. [7][8][9] Moreover, tumor cells usually express activating receptor NKG2D ligands, such as MHC class I chain-related genes A and B (MICA and MICB). It is thought that the interaction between NKG2D and its ligands may enhance the antitumor activity of NK cells. ...
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm treated with tyrosine kinase inhibitors (TKIs). Although survival rates have improved, response to these treatments is highly heterogeneous. Variations in response rates may be due to different causes such as, treatment adherence, mutations in the BCR-ABL1 gene, clonal evolution and amplification of the BCR-ABL1 gene, but innate immune response is also considered to play a very important role and, specifically, NK cell activity through their receptors and ligands, could be determinant.
The aim of this retrospective study was to explore the role of different activating and inhibiting KIR genes as well as the activating NKG2D receptor, present in NK cells, and also their respective ligands, HLA-A, -B, -C, -G, -F, MICA and MICB, in the progression of 190 patients with CML and treated at two hospitals from Barcelona between 2000 and 2019. Early molecular response (EMR), major molecular response (MMR) or MR3.0 and deep molecular response (DMR) or MR4.0 were correlated. As control samples, healthy donors from the Barcelona Blood Bank were analyzed.
The presence of KIR2DL2/KIR2DS2 was associated with the achievement of EMR, MR3.0 and MR4.0. Carriers of the higher expression NKG2D variant and MICA*009:01 were also likely to achieve molecular response (MR). The most remarkable difference between CML patients and controls was a higher frequency of the lower expression NKG2D variant in CML patients.
In summary, our results showed that activating NK receptor phenotypes might help to achieve MR and DMR in CML patients treated with TKIs although confirmatory studies are necessary.
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... As was proved, KIR-HLA class-I affected the antitumor therapy response. Besides, KIR-HLA mismatch (the absence of inhibitory KIR2DL5A, 2DL5B, 2DL5 genes) was correlated with better therapeutic efficacy in CML patients (24), the outcomes of leukemia patients taking hematopoietic stem cell transplantation (HSCT) could be notably improved. Evidence also showed that the KIR-HLA mismatch resulted in a better prognosis for patients undergoing immune therapy involving NK cell function, for example, an anti-GD2 monoclonal antibody (mAb) with the ability to interfere with the HLA-C expression on primary tumor cells (12,14). ...
Natural killer cells (NK cells) play a crucial role in tumor immunity. The function of the NK cells is regulated by various receptors expressed on the surface. Among them, the killer immunoglobulin-like receptor (KIR) is one of the most important. The ligand of KIR is major histocompatibility complex class-I (MHC class-I), which is also called human leukocyte antigen class-I (HLA class-I). The combination of HLA class-I and inhibitory KIRs could inhibit NK cells and induce autoimmune tolerance. Inhibitory KIRs were highly expressed on malignant tumor patients, which were related to poor prognosis. KIR/HLA class-I pathway affected the clinical outcomes of cancer through several mechanisms, and inhibitory KIRs could be an ideal target of immunotherapy strategy.
... There had been few reported about the association between KIR and CML in TKI treatment. Patients who are present with KIR2DS1 [79], KIR2DL2 [80], KIR2DL5A/B genotype [81,82], haplotype Bw and higher numbers of inhibitory KIR genes [80] achieved lower rate of cytogenetic or molecular remission in TKI treatments. Disadvantage of presence with KIR2DS1 existed patients treated with imatinib but not with dasatinib treated [83]. ...
Chronic myelogenous leukemia (CML) is caused by the BCR-ABL chimeric tyrosine kinase, which is derived from the reciprocal translocation, t(9;22)(q34;q11). BCR-ABL tyrosine kinase inhibitors (TKIs) can provide prolonged overall survival in CML patients, resulting in life expectancy nearly to general population, and now approximately
half of patients who achieved deep molecular response (DMR) can sustain durable molecular remission after discontinuation TKIs. However, residual leukemic cells still detected in the patients who sustained in molecular remission after discontinuation TKIs with the sensitive BCL-ABL1 transcript detection method. Given the fact that residual leukemic cells can exist in these patients, host immune systems can protect the patients to develop CML progression derived from residual leukemic cells. The human immune system is generally composed by innate and adaptive immune systems, corresponding to their functional diversities. Natural killer (NK) cells are major components of the innate immune system, while T lymphocytes (T cells) are major components of the adaptive immune system, and both NK cell and T cell mediate immune responses have an important role in CML. Myeloid-derived suppressor cells (MDSCs) that promote expansion of regulatory T cells (Tregs), leading to host immune suppression, are also important. Although regulation mechanism of these immune system has not been fully elucidated, tumor antigen (e.g. Wilms tumor-1), and surface receptors (e.g. killer immunoglobulin-like receptor and natural killer group 2) on NK cells, are pivotal role in these immune system regulations. Hence, we reviewed the current the immunological analysis, especially T cell and NK cell immunity in CML.
... In fact, a more mature and cytotoxic profile was found (CD57 + CD62L − ) in NK cells from MMR treated patients, reestablishing the NK cell functionality that was lost before any treatment ( . Patients treated with dasatinib presented a low expression of inhibitor markers (KIR2DL5A, KIR2DL5B, and KIR2DL5), which were associated with improved molecular response at 12 months of treatment ( Kreutzman et al., 2012). Whereas patients treated with imatinib had an increased expression of NK activating receptors (NKG2D and NKp30, NKp46, NKp80), a recent study has suggested that the reduced expression of NKG2A in NK cells mediated by dasatinib potentiates NK cytotoxic activity and promotes MMR in CML individuals ( Chang et al., 2018). ...
Tyrosine kinase inhibitors (TKIs) of aberrant tyrosine kinase (TK) activity have been widely used to treat chronic myeloid leukemia (CML) for decades in clinic. An area of growing interest is the reported ability of TKIs to induce immunomodulatory effects with anti-tumor and anti-viral activity, which appears to be mediated by directly or indirectly acting on immune cells. In selected cases of patients with CML, TKI treatment may be interrupted and a non-drug remission may be observed. In these patients, an immune mechanism of increased anti-tumor cytotoxic activity induced by chronic administration of TKIs has been suggested. TKIs increase some populations of natural killer (NK), NK-LGL, and T-LGLs cells especially in dasatinib treated CML patients infected with cytomegalovirus (CMV). In addition, dasatinib increases responses against CMV and is able to inhibit HIV replication in vitro. Recent studies suggest that subclinical reactivation of CMV could drive expansion of specific subsets of NK- and T-cells with both anti-tumoral and anti-viral function. Therefore, the underlying mechanisms implicated in the expansion of this increased anti-tumor and anti-viral cytotoxic activity induced by TKIs could be a new therapeutic approach to take into account against cancer and viral infections such as HIV-1 infection. The present review will briefly summarize the immunomodulatory effects of TKIs on T cells, NKs, and B cells. Therapeutic implications for modulating immunity against cancer and viral infections and critical open questions are also discussed.
... 12 The expression of KIR2DL5 has solely been described in CD8 + T cells and CD56 dim NK subset. 13 In the setting of CML, KIR2DL5A and KIR2DL5B genotypes have been associated with a decrease in the rate of 12-month molecular response 14 and 2-year complete cytogenetic response. 15 Recently, the specific KIR2DL5B genotype has been shown to predict a bad prognosis through various outcomes in CML in a first-line imatinib strategy, including transformation-free survival, suggesting an important role in CML immune escape. ...
Background:
Natural Killer (NK) cells are innate lymphoid cells that can be cytotoxic toward a large panel of solid tumors and hematological malignancies including chronic myeloid leukemia (CML). Such a cytotoxicity depends on various receptors. Killer immunoglobulin-like receptors (KIR) belong to these receptors and are involved in maturation process, then in the activation abilities of NK cells.
Methods:
We investigated the prognostic impact of the KIR2DL5B genotype in 240 CML patients included in two clinical trials investigating tyrosine kinase inhibitors (TKI) discontinuation: STIM and STIM2.
Results:
After adjustment for standard risk factors in CML, we found that the inhibitory receptor KIR2DL5B-positive genotype was independently related to a delayed second deep molecular remission (HR 0.54, 95% CI [0.32-0.91], P = 0.02) after TKI rechallenge but not to time to first deep molecular remission or treatment-free remission rates.
Conclusion:
These results suggest that KIR2DL5B could carry a role in lymphocyte-mediated control of leukemic residual disease control in patient with CML relapse.
... In the past few years, the effects of TKI on the NK cell repertoire and function have been analyzed in several studies (28). Of note, increased proportions of terminally differentiated cytolytic CD56 + CD16 + CD57 + NK cells were found in patients that achieved a successful Imatinib therapy discontinuation or in Dasatinib-treated patients with a DMR (12,(29)(30)(31)(32). Recently, it has also been suggested that KIR genotype may represent a new biomarker for response to TKI therapy (33)(34)(35). On the other hand, previous in vitro studies reported conflicting results on the effect of different TKI on NK cell proliferation and function (28). ...
Tyrosin kinase inhibitors (TKI) sharply improved the prognosis of Chronic Myeloid Leukemia (CML) and of Philadelphia⁺ Acute Lymphoblastic Leukemia (Ph⁺ALL) patients. However, TKI are not curative because of the development of resistance and lack of complete molecular remission in the majority of patients. Clinical evidences would support the notion that patient's immune system may play a key role in preventing relapses. In particular, increased proportions of terminally differentiated CD56⁺CD16⁺CD57⁺ NK cells have been reported to be associated with successful Imatinib therapy discontinuation or with a deep molecular response in Dasatinib-treated patients. In view of the potential role of NK cells in immune-response against CML, it is important to study whether any TKI have an effect on the NK cell development and identify possible molecular mechanism(s) by which continuous exposure to in vitro TKI may influence NK cell development and repertoire. To this end, CD34⁺ hematopoietic stem cells (HSC) were cultured in the absence or in the presence of Imatinib, Nilotinib, or Dasatinib. We show that all compounds exert an inhibitory effect on CD56⁺ cell recovery. In addition, Dasatinib sharply skewed the repertoire of CD56⁺ cell population, leading to an impaired recovery of CD56⁺CD117⁻CD16⁺CD94/NKG2A⁺EOMES⁺ mature cytotoxic NK cells, while the recovery of CD56⁺CD117⁺CD94/NKG2A⁻RORγt⁺ IL-22-producing ILC3 was not affected. This effect appears to involve the Dasatinib–mediated inhibition of Src kinases and, indirectly, of STAT5-signaling activation in CD34⁺ cells during first days of culture. Our studies, reveal a possible mechanism by which Dasatinib may interfere with the proliferation and maturation of fully competent NK cells, i.e., by targeting signaling pathways required for differentiation and survival of NK cells but not of ILC3.
... The KIR gene profile is associated with clinical response in patients with chronic myeloid leukemia treated with dasatinib. The absence of the inhibitory KIR2DL5A, 2DL5B, 2DL5all, 2DS1 and 2DS2 genes is associated with improved molecular response at the 12-month time point [44]. Recently, it has been demonstrated that KIR gene haplotype influences the clinical outcome of patients with myelodysplastic syndromes (MDS) and may help to identify MDS patients with a high risk of disease progression to acute myeloid leukemia (AML). ...
Accumulating evidence indicates that the success of cancer therapy depends not only on a combination of adequate procedures (surgery, chemotherapy and radiotherapy) that aim to eliminate all tumor cells, but also on the functional state of the host immune system. HLA and KIR molecules, in particular, are critical to the interactions between tumor cells and both innate and adaptive immune cells such as NK cells and T cells. Different KIR–HLA gene combinations as well as different HLA expression levels on tumor cells associate with variable tumor prognosis and response to treatment. On the other hand, different therapies have different effects on HLA molecules and immune cell functions regulated by these molecules. Here, we provide an overview of the KIR–HLA system, a description of its alterations with clinical relevance in diverse tumor types, and an analysis of the consequences that conventional cancer therapies may have on it. We also discuss how this knowledge can be exploited to identify potential immunological biomarkers that can help to select patients for tailored therapy.
