The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti–PD-1 antibody

Benson, Don M.; Bakan, Courtney E.; Mishra, Anjali; Hofmeister, Craig C.; Efebera, Yvonne A.; Becknell, Brian; Baiocchi, Robert A.; Zhang, Jianying; Yu, Jianhua; Smith, Megan; Greenfield, Carli N; Porcu, Pierluigi; Devine, Steven M.; Rotem-Yehudar, Rinat; Lozanski, Gerard; Byrd, John C.; Caligiuri, Michael A.

doi:10.1182/blood-2010-02-271874

Cited by 710 publications

(692 citation statements)

References 46 publications

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“…The reason is NK cells are mostly devoid of the expression of the checkpoint receptor PD-1; however, the presence of PD-1 + NK cells have been reported in settings of multiple myeloma. 28 In the referenced study, PD-1 inhibition improved NK cell mediated lysis of autologous multiple myeloma cells. Similar to previous reports, PM21-NK cells either expanded ex vivo or isolated from the tumor microenvironment mostly lacked PD-1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of PD-1 blockade on NK cell function has been so far only studied in settings of multiple myeloma where NK cells collected from patients were shown to be positive for PD-1 expression. 28 We have hypothesized that adoptively transferred PM21-NK cells will secrete IFNγ and prime the tumor to induce expression of PD-L1. Since induction of PD-L1 leads to a cascade of events resulting in an immunosuppressive environment, we further postulated that inclusion of PD-L1 blockade will prevent the induction of immunosuppression and improve NK cell efficacy to increase survival of tumor-bearing animals.…”

Section: Introductionmentioning

confidence: 99%

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PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model. Studies here showed that PM21-NK cells secrete high amounts of IFNγ and that adoptively transferred PM21-NK cells induce PD-L1 expression on SKOV-3 cells in vivo. The induction of PD-L1 expression on SKOV-3 cells coincided with the presence of regulatory T cells (Tregs) in the abdominal cavity and within tumors. In in vitro experiments, anti-PD-L1 treatment had no direct effect on cytotoxicity or cytokine secretion by predominantly PD-1 negative PM21-NK cells in response to PD-L1+ targets. However, significant improvement of NK cell anti-tumor efficacy was observed in vivo when combined with anti-PD-L1. PD-L1 blockade also resulted in increased in vivo NK cell persistence and retention of their cytotoxic phenotype. These results support the use of anti-PD-L1 in combination with NK cell therapy regardless of initial tumor PD-L1 status and indicate that NK cell therapy would likely augment the applicability of anti-PD-L1 treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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“…In multiple myeloma patients, tumor-associated NK cells were shown to express PD-1. Upon PD-1 blockade, increased killing of B7-H1-expressing tumor cells by NK cells was observed [82]. CTLA-4 inhibits the function of both T cells [83] and NK cells (our unpublished observation) underlining its importance as a therapeutic target.…”

Section: Shaping Of Nk Cell Function By the Tumor Microenvironmentmentioning

confidence: 70%

Shaping of NK Cell Responses by the Tumor Microenvironment

Stojanović

Correia

Cerwenka

2012

Cancer Microenvironment

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Natural killer (NK) cells belong to the innate immune system and are potent cytolytic and cytokineproducing effector cells in response to tumor targets. NK cell based anti-tumor immunotherapy was so far mainly successful in patients with different types of leukemia. For instance, acute myeloid leukemia (AML) patients displayed a prolonged survival if transplanted with haploidentical stem cells giving rise to NK cells with a mismatch in inhibitory killer immunoglobulin receptors (KIRs) and recipients' HLA class I. Although promising results have been achieved with hematological tumors, solid tumors are in most cases poorly controlled by NK cells. Therapeutic protocols that aimed at improving NK cell responses in patients with solid malignancies succeeded in increasing NK cell numbers and functional responses of NK cells isolated from the patients' peripheral blood. However, in the majority of cases tumor progression and overall survival of patients were not significantly improved. There is increasing evidence that tumor-associated NK cells become gradually impaired during tumor progression compared to NK cells from peripheral blood and healthy tissues. Future protocols of NK cell based immunotherapy should integrate three important aspects to improve NK cell anti-tumor activity: facilitating NK cell migration to the tumor site, enhancing their infiltration into the tumor tissue and ensuring subsequent efficient activation in the tumor. This review summarizes the current knowledge of tumor-infiltrating NK cells and the influence of the tumor microenvironment on their phenotype and function.

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“…Benson et al reported that monoclonal antibody anti-PD-1 could be a novel immunotherapy for MM because its inhibition upregulates T-cell activation and immune response [23]. Accordingly, the relationship between PD-1 and novel prognostic factor CD200 should be considered.…”

Section: Erçetin Et Al T Regulatory Cells In Multiple Myelomamentioning

confidence: 99%

The correlation between T regulatory cells and autologous peripheral blood stem cell transplantation in multiple myeloma

Ercetin

Aktaş²,

Pişkin³

et al. 2011

Turk J Hematol

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Objective: Multiple myeloma (MM) is characterized by malignant proliferation of plasmocytes and their precursors. T regulatory cells (Tregs) have a role in immunosuppression and control of autoimmunity, and are currently an important topic in the study of immune response to tumor cells. The correlation between Tregs and autologous peripheral blood stem cell transplantation (APBSCT) in MM has not been studied. The aim of this study was to compare CD4+CD25+FOXP3+ Treg, CD200, and PD-1 levels in MM patients that did and did not undergo APBSCT. Materials and Methods: Peripheral blood samples were collected from 28 MM patients ranging in age from 41 to 78 years for analysis of CD4CD25+ FOXP3+ Tregs, PD-1 (CD279), and CD200. Peripheral blood mononuclear cells were isolated via density gradient centrifugation. Four-color flow cytometry was performed. Using a sequential gating strategy, Tregs were identified as CD4+CD25+FOXP3+ T-cells. Results were analyzed using the Mann Whitney U non-parametric test and a compare means test. p values <0.05 were considered statistically significant. Results: The study included 28 MM patients (10 female and 18 male). In all, 11 of the patients underwent APBSCT. The level of Tregs identified as CD4+CD25+FOXP3+ T-cells was higher in the patients that underwent APBSCT (p=0.042). CD200 and PD-1 levels did not significantly differ between the 2 groups (p=0.711 and p=0.404, respectively). There weren't any statistically significant differences in CD200, PD-1, or CD4+CD25+FOXP3+ T-cell levels between the patients that did and did not undergo APBSCT (p>0.05). Conclusion: Treg levels were higher in the patients that underwent APBSCT. Tregs are crucial for the induction and maintenance of peripheral tolerance to self-antigens. In addition, Tregs can suppress immune responses to tumor antigens; however, APBSCT and Treg levels were not correlated with CD200 or PD-1 expression. Relationship of Tregs with prognosis needs to be determined by studies that include larger cohorts. (Turk J Hematol 2011; 28: 107-14)

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The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti–PD-1 antibody

Cited by 710 publications

References 46 publications

PD-L1 blockade enhances anti-tumor efficacy of NK cells

PD-L1 blockade enhances anti-tumor efficacy of NK cells

Shaping of NK Cell Responses by the Tumor Microenvironment

The correlation between T regulatory cells and autologous peripheral blood stem cell transplantation in multiple myeloma

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