Multiplex and Genome-Wide Analyses Reveal Distinctive Properties of KIR+ and CD56+ T Cells in Human Blood

Chan, Wing Keung; Rujkijyanont, Piya; Neale, Geoffrey; Yang, Jie; Bari, Rafijul; Gupta, Neha; Holladay, Martha; Rooney, Barbara; Leung, Wing

doi:10.4049/jimmunol.1300111

Cited by 56 publications

(83 citation statements)

References 74 publications

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“…Because the population of KIR − and unlicensed NK cells within the total NK cell repertoire is large, rituximab’s ability to activate these previously tolerant, hypo-responsive NK cells may be a fundamental mechanism contributing to the rituximab clinical responses. Our analysis of the NK cell repertoire is consistent with the literature, demonstrating significant inter-individual variability in spKIR + and KIR − NKG2A − NK cell populations (11, 12, 21, 31, 38, 43). By combining single-cell exclusion gating with KIR phenotyping, HLA genotyping and HLA class I KIR ligand assignment, we also demonstrate that licensed NK cells may comprise a minority of the NK cell population, depending on an individual’s HLA genotype.…”

Section: Discussionsupporting

confidence: 90%

CALGB 150905 (Alliance): Rituximab Broadens the Antilymphoma Response by Activating Unlicensed NK Cells

López‐Vergès

Pitcher

et al. 2014

Cancer Immunology Research

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Natural killer (NK) cells contribute to clinical responses in patients treated with rituximab, but the rules determining NK cell responsiveness to mAb therapies are poorly defined. A deeper understanding of the mechanisms responsible for antibody-dependent cellular cytotoxicity (ADCC) could yield useful biomarkers for predicting clinical responses in patients. Unlicensed NK cells, defined as NK cells lacking expression of an inhibitory KIR for self-HLA class I ligands, are hypo-responsive in steady-state, but are potent effectors in inflammatory conditions. We hypothesized that antitumor antibodies such as rituximab can overcome NK cell dependence on licensing, making unlicensed NK cells important for clinical responses. Here we examined the influences of variations in KIR and HLA class I alleles on in vitro responses to rituximab. We tested the clinical significance in a cohort of follicular lymphoma patients treated with rituximab-containing mAb combinations and show that rituximab triggers responses from all NK cell populations regardless of licensing. Neither IL-2 nor accessory cells are required for activating unlicensed NK cells, but both can augment rituximab-mediated ADCC. Moreover, in 101 follicular lymphoma patients treated with rituximab-containing mAb combinations, a “missing ligand” genotype (predictive of unlicensed NK cells) is associated with higher progression-free survival. Our data suggest that the clinical efficacy of rituximab may be driven, in part, by its ability to broaden the NK cell repertoire to include previously hypo-responsive, unlicensed NK cells. A “missing ligand” KIR and HLA class I genotype may be predictive of this benefit, and useful for personalizing treatment decisions in lymphomas and other tumors.

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Section: Discussionsupporting

confidence: 90%

CALGB 150905 (Alliance): Rituximab Broadens the Antilymphoma Response by Activating Unlicensed NK Cells

López‐Vergès

Pitcher

et al. 2014

Cancer Immunology Research

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“…Among known NK receptors, the KIR receptor family is one of the primary determinants of NK response. Subsets of T cells also expressed KIR (21). Clinical KIR typing includes genotyping for gene content and A/B haplotype categorization, phenotyping for gene expression and number of KIR þ cells, and allelotyping for functional strength.…”

Section: Regulatory Receptorsmentioning

confidence: 99%

Infusions of Allogeneic Natural Killer Cells as Cancer Therapy

Leung

2014

Clinical Cancer Research

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Natural killer (NK) cells are normal white blood cells capable of killing malignant cells without prior sensitization. Allogeneic NK cell infusions are attractive for cancer therapy because of non-cross-resistant mechanisms of action and minimal overlapping toxicities with standard cancer treatments. Although NK therapy is promising, many obstacles will need to be overcome, including insufficient cell numbers, failure of homing to tumor sites, effector dysfunction, exhaustion, and tumor cell evasion. Capitalizing on the wealth of knowledge generated by recent NK cell biology studies and the advancements in biotechnology, substantial progress has been made recently in improving therapeutic efficiency and reducing side effects. A multipronged strategy is essential, including immunogenetic-based donor selection, refined NK cell bioprocessing, and novel augmentation techniques, to improve NK function and to reduce tumor resistance. Although data from clinical trials are currently limited primarily to hematologic malignancies, broader applications to a wide spectrum of adult and pediatric cancers are under way. The unique properties of human NK cells open up a new arena of novel cell-based immunotherapy against cancers that are resistant to contemporary therapies. Clin Cancer Res; 20(13); 3390-400. Ó2014 AACR.

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“…Several studies have described CD56 ϩ T cell implication in HCMV infection (23)(24)(25)(26). Similar to NK and conventional cells and ␥␦ T lymphocytes in PHIP, CD56 ϩ T cells appear to be activated, as shown by the strong increase in CD38-expressing CD56 ϩ T cells in PHIP compared to HCMV Ϫ (P Ͻ 0.0001) and HCMV ϩ (P Ͻ 0.0001) individuals (Fig.…”

mentioning

confidence: 75%

Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

Riou

Bressollette-Bodin

Boutoille³

et al. 2017

J Virol

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Primary human cytomegalovirus (HCMV) infection usually goes unnoticed, causing mild or no symptoms in immunocompetent individuals. However, some rare severe clinical cases have been reported without investigation of host immune responses or viral virulence. In the present study, we investigate for the first time phenotypic and functional features, together with gene expression profiles in immunocompetent adults experiencing a severe primary HCMV infection. Twenty primary HCMV-infected patients (PHIP) were enrolled, as well as 26 HCMVseronegative and 39 HCMV-seropositive healthy controls. PHIP had extensive lymphocytosis marked by massive expansion of natural killer (NK) and T cell compartments. Interestingly, PHIP mounted efficient innate and adaptive immune responses with a deep HCMV imprint, revealed mainly by the expansion of NKG2C ϩ NK cells, CD16 ϩ V␦2(Ϫ) ␥␦ T cells, and conventional HCMV-specific CD8 ϩ T cells. The main effector lymphocytes were activated and displayed an early immune phenotype that developed toward a more mature differentiated status. We suggest that both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage observed in PHIP. Taken together, these findings bring new insights into the comprehensive understanding of immune mechanisms involved during primary HCMV infection in immunocompetent individuals.IMPORTANCE HCMV-specific immune responses have been extensively documented in immunocompromised patients and during in utero acquisition. While it usually goes unnoticed, some rare severe clinical cases of primary HCMV infection have been reported in immunocompetent patients. However, host immune responses or HCMV virulence in these patients has not so far been investigated. In the present study, we show massive expansion of NK and T cell compartments during the symptomatic stage of acute HCMV infection. The patients mounted efficient innate and adaptive immune responses with a deep HCMV imprint. The massive lymphocytosis could be the result of nonadapted or uncontrolled immune responses limiting the effectiveness of the specific responses mounted. Both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage. Furthermore, we cannot exclude a delayed immune response caused by immune escape established by HCMV strains.

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Multiplex and Genome-Wide Analyses Reveal Distinctive Properties of KIR+ and CD56+ T Cells in Human Blood

Cited by 56 publications

References 74 publications

CALGB 150905 (Alliance): Rituximab Broadens the Antilymphoma Response by Activating Unlicensed NK Cells

CALGB 150905 (Alliance): Rituximab Broadens the Antilymphoma Response by Activating Unlicensed NK Cells

Infusions of Allogeneic Natural Killer Cells as Cancer Therapy

Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

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