Mechanisms of NK cell dysfunction in the tumor microenvironment and current clinical approaches to harness NK cell potential for immunotherapy

Devillier, Raynier; Chrétien, Anne-Sophie; Pagliardini, Thomas; Salem, N.; Blaise, Didier; Olive, Daniel

doi:10.1002/jlb.5mr0920-198rr

Cited by 32 publications

(30 citation statements)

References 247 publications

(505 reference statements)

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“…At the same time, the expression of inhibitory receptors recognizing Human Leukocyte Antigen (HLA) class I molecules allows NK cells to spare healthy cells and selectively kill those that underwent malignant transformation and may have lost HLA class I expression [2]. The central role of NK cells in tumour clearance and maintenance of long-term remissions is highlighted by studies showing that NK cell alterations in the tumor microenvironment (TME) are associated with adverse clinical outcomes [3]. NK cell dysfunction is associated with significant phenotypic alterations, including a decreased expression of the natural cytotoxicity receptors (NCRs) in solid tumors and hematological malignancies, and the downregulation of the activating receptors DNAX Accessory Molecule-1 (DNAM-1) and Natural Killer Group 2D (NKG2D) [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

Quatrini

Mariotti

Munari

et al. 2020

Cancers

110

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In the last years, immunotherapy with antibodies against programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) has shown remarkable efficacy in the treatment of different types of tumours, representing a true revolution in oncology. While its efficacy has initially been attributed only to unleashing T cell responses, responsivity to PD-1/PD-L1 blockade was observed in some tumours with low Human Leukocyte Antigen (HLA) I expression and increasing evidence has revealed PD-1 surface expression and inhibitory function also in natural killer (NK) cells. Thus, the contribution of anti-PD-1/PD-L1 therapy to the recovery of NK cell anti-tumour response has recently been appreciated. Here, we summarize the studies investigating PD-1 expression and function in NK cells, together with the limitations and perspectives of immunotherapies. A better understanding of checkpoint biology is needed to design next-generation therapeutic strategies and to improve the clinical protocols of current therapies.

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Section: Introductionmentioning

confidence: 99%

The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

Quatrini

Mariotti

Munari

et al. 2020

Cancers

110

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“…NK cells are the rst activated immune cells in anti-tumor immunity and important cytotoxic cells in the innate immunity, which can be activated and exert their effector functions without antigenic stimulation [26]. The decreased number of NK cells indicates that the immune system is less capable of monitoring, killing, and clearing tumor cells [27]. Hence, the detection of the ACL in tumor patients is of great signi cance for understanding the changes of patients' condition and prognosis [28].…”

Section: Discussionmentioning

confidence: 99%

Absolute Counts of Peripheral Lymphocyte Subsets as Potential Immune Impairment Markers in Patients With Breast Cancer

Liu¹,

Xia²,

Li³

et al. 2021

Preprint

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Purpose This study was to evaluate clinic value of absolute counts of lymphocyte subsets (ACL) as potential blood biomarkers in progression and prognosis in breast cancer (BC) patients.Methods A total of 237 BC patients and 55 age-matched female normal healthy donors (normal cantrals, NCs) were enrolled in this study. The absolute counts (AC) and percentages of CD3+, CD3+CD4+, CD3+CD8+, B and NK cells were determined by flow cytometry. The clinicopathological parameters influencing disease progression were determined by binary logistic regression. The progression-free survival (PFS) was evaluated by Kaplan-Meier. Univariable and multivariable analyses were performed using log-rank test and proportional hazard regression models, respectively.Results Compared with NCs, the ACL in BC patients decreased significantly, while the percentages of lymphocytes showed no change. Of them, AC of CD3+CD4+ cells was closely related to clinical stages. The ACL, especially CD3+CD4+ cells, were affected by different treatments. Analysis of logistic regression showed that the cut-off value of CD3+CD4+ cells ≥ 451 cells/μL was the favorable prognostic factor. Multivariate analysis of prognostic factors of PFS showed CD3+CD4+ and CD3+CD8+ cells were independent factors for predicting PFS.Conclusions The AC of CD3+, CD3+CD4+, CD3+CD8+, B, and NK cells in BC patients were impaired obviously and can be as potential susceptive indications to evaluate the patient's immune states. The higher level of AC of CD3+CD4+ and CD3+CD8+ cells contributed to longer PFS and favorable outcome, and could help to adopt appropriate treatment strategies in clinic.

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“…Elevated levels of estrogens promote proteinase inhibitor 9 expression, which protects breast cancer cells from granzyme B-induced apoptosis in vitro ( 156 ). For a more detailed review of additional tumoral mechanisms shaping NK cell anti-tumor functions, see ( 144 , 157 , 158 ) .…”

Section: Mechanisms Driving Nk Cell Dysfunctionmentioning

confidence: 99%

Natural Killer Cells: The Linchpin for Successful Cancer Immunotherapy

2021

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Cancer immunotherapy is a highly successful and rapidly evolving treatment modality that works by augmenting the body’s own immune system. While various immune stimulation strategies such as PD-1/PD-L1 or CTLA-4 checkpoint blockade result in robust responses, even in patients with advanced cancers, the overall response rate is low. While immune checkpoint inhibitors are known to enhance cytotoxic T cells’ antitumor response, current evidence suggests that immune responses independent of cytotoxic T cells, such as Natural Killer (NK) cells, play crucial role in the efficacy of immunotherapeutic interventions. NK cells hold a distinct role in potentiating the innate immune response and activating the adaptive immune system. This review highlights the importance of the early actions of the NK cell response and the pivotal role NK cells hold in priming the immune system and setting the stage for successful response to cancer immunotherapy. Yet, in many patients the NK cell compartment is compromised thus lowering the chances of successful outcomes of many immunotherapies. An overview of mechanisms that can drive NK cell dysfunction and hinder immunotherapy success is provided. Rather than relying on the likely dysfunctional endogenous NK cells to work with immunotherapies, adoptive allogeneic NK cell therapies provide a viable solution to increase response to immunotherapies. This review highlights the advances made in development of NK cell therapeutics for clinical application with evidence supporting their combinatorial application with other immune-oncology approaches to improve outcomes of immunotherapies.

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Mechanisms of NK cell dysfunction in the tumor microenvironment and current clinical approaches to harness NK cell potential for immunotherapy

Cited by 32 publications

References 247 publications

The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

Absolute Counts of Peripheral Lymphocyte Subsets as Potential Immune Impairment Markers in Patients With Breast Cancer

Natural Killer Cells: The Linchpin for Successful Cancer Immunotherapy

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