Expression of the Activating Receptor, NKp46 (CD335), in Human Natural Killer and T-Cell Neoplasia

Freud, Aharon G.; Song, Zhao; Wei, Sibing; Gitana, Gary M.; Molina-Kirsch, Hernan; Atwater, Susan K.; Natkunam, Yasodha

doi:10.1309/ajcpwgg69mczowmm

Cited by 37 publications

(24 citation statements)

References 49 publications

(53 reference statements)

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“…The NK cell population diversity studies described above are in line with numerous other reports that changes in NK cell surface marker expression and relative KIR + NK cell frequencies occur in the settings of cancer and infection (Beziat et al, 2012; Beziat et al, 2013; Davis et al, 2015; Fauriat et al, 2007; Freud et al, 2013; Guma et al, 2004; Guma et al, 2006; Sun et al, 2012). Many such studies were originally performed and interpreted in the conceptual framework of the traditional CD56 bright and CD56 dim cNK dichotomy.…”

Section: Adaptive Nk Cellssupporting

confidence: 87%

The Broad Spectrum of Human Natural Killer Cell Diversity

et al. 2017

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SUMMARY Natural killer (NK) cells provide protection against infectious pathogens and cancer. For decades it has been appreciated that two major NK cell subsets (CD56bright and CD56dim) exist in humans and have distinct anatomical localization patterns, phenotypes, and functions in immunity. In light of this traditional NK cell dichotomy, it is now clear that the spectrum of human NK cell diversity is much broader than originally appreciated as a result of variegated surface receptor, intracellular signaling molecule, and transcription factor expression; tissue-specific imprinting; and foreign antigen exposure. The recent discoveries of tissue-resident NK cell developmental intermediates, non-NK innate lymphoid cells, and the capacity for NK cells to adapt and differentiate into long-lived memory cells has added further complexity to this field. Here we review our current understanding of the breadth and generation of human NK cell diversity.

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Section: Adaptive Nk Cellssupporting

confidence: 87%

The Broad Spectrum of Human Natural Killer Cell Diversity

et al. 2017

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“…This molecule may function in cell‐cell interactions in addition to its cytotoxic effects in the tumor environment. Recent study showed that NKp46 was detected in ALK + ALCL cells but not in EATL cells . Nevertheless, we observed that NKp46 was detected in some of the surrounding bystander cells but not in ALK + ALCL cells (Figure C).…”

Section: Discussioncontrasting

confidence: 52%

“…Previous studies showed that CD94, NKG2A, and NKp46 were usually detected in ENKL, whereas the expression of another group of NKR, the killer cell immunoglobulin‐like receptors seem to be reduced in most ENKL cases . The pathological implication of NKR in PTNKL remains to be defined.…”

Section: Introductionmentioning

confidence: 95%

Expression of activating natural killer‐cell receptors is a hallmark of the innate‐like T‐cell neoplasm in peripheral T‐cell lymphomas

et al. 2018

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Peripheral T‐ or natural killer (NK)‐cell lymphomas are rare and difficult‐to‐recognize diseases. It remains arduous to distinguish between NK cell‐ and cytotoxic T‐lymphocyte‐derived lymphomas through routine histological evaluation. To clarify the cells of origin, we focused on NK‐cell receptors and examined the expression using immunohistochemistry in 22 cases with T‐ and NK‐cell neoplasms comprising angioimmunoblastic T‐cell lymphoma, anaplastic lymphoma kinase (ALK)‐positive and ‐negative anaplastic large‐cell lymphomas, extranodal NK/T‐cell lymphoma, nasal type, monomorphic epitheliotropic intestinal T‐cell lymphoma, aggressive NK‐cell leukemia, and other peripheral T‐cell lymphomas. Inhibitory receptor leukocyte immunoglobulin‐like receptor subfamily B member 1 (LILRB1) was detected in 14 (64%) cases, whereas activating receptors DNAM1, NKp46, and NKG2D were expressed in 7 (32%), 9 (41%), and 5 (23%) cases, respectively. Although LILRB1 was detected regardless of the disease entity, the activating NK‐cell receptors were expressed predominantly in TIA‐1‐positive neoplasms (DNAM1, 49%; NKp46, 69%; and NKG2D, 38%). In addition, NKp46 and NKG2D were detected only in NK‐cell neoplasms and cytotoxic T‐lymphocyte‐derived lymphomas including monomorphic epitheliotropic intestinal T‐cell lymphoma. One Epstein‐Barr virus‐harboring cytotoxic T‐lymphocyte‐derived lymphoma mimicking extranodal NK/T‐cell lymphoma, nasal type lacked these NK‐cell receptors, indicating different cell origin from NK and innate‐like T cells. Furthermore, NKG2D expression showed a negative impact on survival among the 22 examined cases, which mainly received the standard chemotherapy regimen (log‐rank test, P = .024). We propose that the presence of activating NK‐cell receptors may provide new insights into understanding peripheral T‐cell lymphomas and characterizing them as innate‐like T‐cell neoplasm.

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“…NKp46 has been implicated as either a critical player in the progression and severity of different diseases, including type I diabetes, or as a prognostic marker in NK cell malignancies , and approximately 20% of T cell lymphomas . Consequently, we wanted to investigate whether our antibody has the potential to become a novel immunotherapeutic drug for the treatment of these diseases.…”

Section: Resultsmentioning

confidence: 99%

Human anti‐NKp46 antibody for studies of NKp46‐dependent NK cell function and its applications for type 1 diabetes and cancer research

Berhani¹,

Glasner²,

Kahlon³

et al. 2018

Eur J Immunol

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Natural killer (NK) cells are innate lymphocytes that efficiently eliminate cancerous and infected cells. NKp46 is an important NK activating receptor shown to participate in recognition and activation of NK cells against pathogens, tumor cells, virally infected cells, andself-cells in autoimmune conditions, including type I and II diabetes. However, some of the NKp46 ligands are unknown and therefore investigating human NKp46 activity and its critical role in NK cell biology is problematic. We developed a unique anti-human NKp46 monocloncal antibody, denoted hNKp46.02 (02). The 02 mAb can induce receptor internalization and degradation. By binding to a unique epitope on a particular domain of NKp46, 02 lead NKp46 to lysosomal degradation. This downregulation therefore enables the investigation of all NKp46 activities. Indeed, using the 02 mAb we determined NK cell targets which are critically dependent on NKp46 activity, including certain tumor cells lines and human pancreatic beta cells. Most importantly, we showed that a toxinconjugated 02 inhibits the growth of NKp46-positive cells; thus, exemplifying the potential of 02 in becoming an immunotherapeutic drug to treat NKp46-dependent diseases, such as, type I diabetes and NK and T cell related malignancies.Keywords: NK cells r NKp46 r antibody r cancer r type 1 diabetes Additional supporting information may be found online in the Supporting Information section at the end of the article.

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Expression of the Activating Receptor, NKp46 (CD335), in Human Natural Killer and T-Cell Neoplasia

Abstract: Collectively, these data support the diagnostic utility of CD335 in evaluating hematopoietic malignancies and suggest that CD335 could be a useful target for selective immunotherapy in patients with mature NK and T-cell neoplasms.

Cited by 37 publications

References 49 publications

The Broad Spectrum of Human Natural Killer Cell Diversity

The Broad Spectrum of Human Natural Killer Cell Diversity

Expression of activating natural killer‐cell receptors is a hallmark of the innate‐like T‐cell neoplasm in peripheral T‐cell lymphomas

Human anti‐NKp46 antibody for studies of NKp46‐dependent NK cell function and its applications for type 1 diabetes and cancer research

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