Novel Targets for Natural Killer/T-cell Lymphoma Immunotherapy

Kumai, Takumi; Kobayashi, Hiroya; Harabuchi, Yasuaki

doi:10.2217/imt.15.103

Cited by 6 publications

(7 citation statements)

References 85 publications

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“…The results showed that the expression of ABCC4 in SNK-6/ADM and SNK-6/ADM-SP were both higher than that in SNK-6, while the ABCG2 expression was significantly increased in SNK-6/ADM-SP cells. What was more, we considered that the main factor underlying SNK-6/ADM drug resistance was ABCC4 and ABCG2 rather than P-gp, which is the most classic MDR protein, and consistent with recent studies [ 4 , 25 ] suggesting the absence of absolute correlation between P-gp and chemotherapy resistance. Further results showed that the doxorubicin resistance in SNK-6/ADM-SP cells transfected with shRNAs targeting ABCC4, ABCG2 and ABCC4 + ABCG2 was significantly decreased compared with the sh-control groups, indicating the vital roles of ABCC4 in drug resistance and ABCG2 in conservative characteristics of SNK-6/ADM-SP cells.…”

Section: Discussionsupporting

confidence: 84%

“…Current treatment strategies are not effective and chemoresistance leads to poor prognosis [ 5 , 14 ]. The mechanism of oncogenesis and biological characteristics of ENKL which provide important insights into potential therapeutic options is not clear [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

“…Epstein–Barr virus (EBV) is usually detected in ENKL cells and plays an important role in lymphomagenesis. In most ENKL cases, the disease leads to significant chemotherapy resistance and poor clinical outcomes, probably due to the expression of multidrug-resistant genes and close association with EBV infection [ 3 , 4 ]. Treatment regimens containing l -asparaginase ( l -ASP) or pegaspargase have elicited promising responses [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Conserved cell populations in doxorubicin-resistant human nasal natural killer/T cell lymphoma cell line: super multidrug resistant cells?

Zhang¹,

Fu²,

Meng³

et al. 2018

Cancer Cell Int

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BackgroundExtranodal NK/T-cell lymphoma, nasal type (ENKL) is a distinct clinicopathological entity and EBV-associated disease that is highly aggressive. Many patients had failed to respond to conventional chemotherapy or relapsed after treatment. Multi-drug resistance is a major cause that leads to these desperate failures. However, the specific mechanism of drug resistance is still unclear.MethodsIn the previous study, we firstly developed a doxorubicin-resistant ENKL cell line known as SNK-6/ADM, and then a small quantity of side population (SP) cells were derived from SNK-6/ADM and named SNK-6/ADM-SP. In order to explore the biological characteristics and mechanism of drug-resistance of these cells, SNK-6, SNK-6/ADM and SNK-6/ADM-SP cells were utilized to evaluate potentially differences of chemotherapy resistance index (RI), morphology, proliferation, cell cycles, expression of ATP-binding cassette (ABC) transporters (ABCG1, ABCG2 and ABCC4) and surface markers, cytokine sensitivity, and situation of EBV infection.ResultsWe identified SNK-6/ADM-SP is a specific multidrug resistant cell population with a higher level of RI than SNK-6/ADM. Relevant evaluations showed that SNK-6/ADM-SP presented a series of conserved biological behaviors including relatively poor proliferation ability, high expression of ABCG2, weak sensitivity to IL-15 which could stimulate normal ENKL cells’ proliferation and differentiation, and EBV inhibition with low level of EBV-DNA replication and EBV-antigen expression.ConclusionsThis discovered cellular heterogeneity of ENKL could provide a new perspective to better understand the mechanisms of drug resistance and overcome elusive response to chemotherapy of ENKL.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Conserved cell populations in doxorubicin-resistant human nasal natural killer/T cell lymphoma cell line: super multidrug resistant cells?

Zhang¹,

Fu²,

Meng³

et al. 2018

Cancer Cell Int

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“…The combination of c-Met or checkpoint blockade with peptide vaccine would be an attracting treatment option in NNKTL. The potential of immunotherapy against NNKTL has been summarized in a review article (112). Because NNKTL is an EBV-related disease, gene therapy to knockout EBV-related proteins or miR would be a fundamental solution to remove NNKTL cells.…”

Section: Establishment Of Novel Treatments For Nnktlmentioning

confidence: 99%

Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: Basic Science and Clinical Progress

et al. 2019

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Extranodal natural killer (NK)/T-cell lymphoma, nasal type (NNKTL) has very unique epidemiological, etiologic, histologic, and clinical characteristics. It is commonly observed in Eastern Asia, but quite rare in the United States and Europe. The progressive necrotic lesions mainly in the nasal cavity, poor prognosis caused by rapid local progression with distant metastases, and angiocentric and polymorphous lymphoreticular infiltrates are the main clinical and histologic features. Phenotypic and genotypic studies revealed that the lymphoma is originated from either NK- or γδ T-cell, both of which express CD56. In 1990, the authors first reported the presence of Epstein-Barr virus (EBV)-DNA and EBV-oncogenic proteins, and EBV has now been recognized to play an etiological role in NNKTL. in vitro studies revealed that a wide variety of cytokines, chemokines, and micro RNAs, which may be produced by EBV-oncogenic proteins in the lymphoma cells, play important roles for tumor progression in NNKTL, and could be therapeutic targets. In addition, it was revealed that the interaction between NNKTL cells and immune cells such as monocytes and macrophages in NNKTL tissues contribute to lymphoma progression. For diagnosis, monitoring the clinical course and predicting prognosis, the measurements of EBV-DNAs and EBV-micro RNAs in sera are very useful. For treatment with early stage, novel concomitant chemoradiotherapy such as DeVIC regimen with local radiotherapy and MPVIC-P regimen using intra-arterial infusion developed with concomitant radiotherapy and the prognosis became noticeably better. However, the prognosis of patients with advanced stage was still poor. Establishment of novel treatments such as the usage of immune checkpoint inhibitor or peptide vaccine with molecular targeting therapy will be necessary. This review addresses recent advances in the molecular understanding of NNKTL to establish novel treatments, in addition to the epidemiologic, clinical, pathological, and EBV features.

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“…In the past 10 years, survival of patients has been improved greatly by antibodies targeting immune checkpoints in a number of human cancers, such as melanoma, renal cancer, colon cancer, and lung cancer. NKTCL might also be targetable for therapeutic antibodies owing to 67% of NKTCL samples expressing PD-L1 [ 17 ]. Lastly, Kwong et al [ 18 ] reported high efficacy of pembrolizumab in relapsed/refractory NKTCL that failed on L-asparaginase.…”

Section: Discussionmentioning

confidence: 99%

Successful treatment with anti-programmed-death-1 antibody in a relapsed natural killer/T-cell lymphoma patient with multi-line resistance: a case report

Lai

Jiang

et al. 2017

BMC Cancer

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BackgroundExtranodal natural killer/T-cell lymphoma (NKTCL), nasal type, is an aggressive malignancy with poor prognosis. Currently, there is no recommended standard therapy for relapsed NKTCL.Case presentationA 37-year-old woman with lymphadenopathy was diagnosed with NKTCL by biopsy of an enlarged lymph node on the right side of her neck. Enhanced computed tomography revealed no metastasis. For this patient, we performed continuous chemotherapy followed by radiotherapy; however, nodule biopsy showed metastases in her lower limbs 3 months after radiotherapy, which confirmed disease progression. Unfortunately, the patient’ s temperature was persistently high and her skin ulcers could not be controlled well using multi-line treatment. Therefore, we attempted treatment with the anti-programmed-death-1 (PD-1) antibody, pembrolizumab. Surprisingly, the patient achieved clinical complete remission (CR) after four cycles of pembrolizumab treatment, despite having persistent detectable Epstein-Barr virus (EBV) DNA. Other molecular monitoring techniques were unavailable for this patient owing to the retrospective nature of the study. The only adverse event was soreness of the upper limb joints and muscles.ConclusionThis relapsed NKTCL case treated with pembrolizumab showed that multimodal therapy including pembrolizumab would be partially or totally effective for relapsed NKTCL.

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Novel Targets for Natural Killer/T-cell Lymphoma Immunotherapy

Cited by 6 publications

References 85 publications

Conserved cell populations in doxorubicin-resistant human nasal natural killer/T cell lymphoma cell line: super multidrug resistant cells?

Conserved cell populations in doxorubicin-resistant human nasal natural killer/T cell lymphoma cell line: super multidrug resistant cells?

Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: Basic Science and Clinical Progress

Successful treatment with anti-programmed-death-1 antibody in a relapsed natural killer/T-cell lymphoma patient with multi-line resistance: a case report

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