The Role of Natural Killer T Cells in Cancer—A Phenotypical and Functional Approach

Krijgsman, Daniëlle; Hokland, Marianne; Kuppen, Peter J.K.

doi:10.3389/fimmu.2018.00367

Cited by 181 publications

(197 citation statements)

References 270 publications

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“…After MACS isolation, we also observed a CD3 + CD56 − population, indicating that a subpopulation of NKT cells does not express CD56, which is already known and described in the literature [33]. Thus, the total amount of pure NKT cells is most likely higher in our study.…”

Section: Discussionsupporting

confidence: 74%

The Generation of CAR-Transfected Natural Killer T Cells for the Immunotherapy of Melanoma

Simon

Wiesinger

März

et al. 2018

IJMS

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Natural killer T (NKT) cells represent a cell subpopulation that combines characteristics of natural killer (NK) cells and T cells. Through their endogenous T-cell receptors (TCRs), they reveal a pronounced intrinsic anti-tumor activity. Thus, a NKT cell transfected with a chimeric antigen receptor (CAR), which recognizes a tumor-specific surface antigen, could attack tumor cells antigen-specifically via the CAR and additionally through its endogenous TCR. NKT cells were isolated from peripheral blood mononuclear cells (PBMCs), expanded, and electroporated with mRNA encoding a chondroitin sulfate proteoglycan 4 (CSPG4)-specific CAR. The CAR expression on NKT cells and their in vitro functionality were analyzed. A transfection efficiency of more than 80% was achieved. Upon stimulation with melanoma cells, CAR-NKT cells produced cytokines antigen-specifically. Compared with conventional CAR-T cells, cytokine secretion of CAR-NKT cells was generally lower. Specific cytotoxicity, however, was similar with CAR-NKT cells showing a trend towards improved cytotoxicity. Additionally, CAR-NKT cells could kill target cells through their endogenous TCRs. In summary, it is feasible to generate CAR-NKT cells by using mRNA electroporation. Their CAR-mediated cytotoxicity is at least equal to that of conventional CAR-T cells, while their intrinsic cytotoxic activity is maintained. Thus, CAR-NKT cells may represent a valuable alternative to conventional CAR-T cells for cancer immunotherapy.

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Section: Discussionsupporting

confidence: 74%

The Generation of CAR-Transfected Natural Killer T Cells for the Immunotherapy of Melanoma

Simon

Wiesinger

März

et al. 2018

IJMS

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“…In the early stages of cancer development, NKT cells may promote the maturation of dendritic cells and even assume a T helper 1 phenotype to induce an effective antitumor response. In contrast, when chronically stimulated, these cells can become anergic and switch to a T helper 2/T regulatory profile, to promote M2 macrophage polarization and facilitate immune escape and consequent tumour progression 95 . Based on our findings regarding NKT cells and M2 macrophages and on the evidence that endometriosis is a chronic inflammatory disease, at least the later stages, we hypothesised that the anergy of NKT cells may promote M2 macrophage polarization in the eutopic endometrium.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome meta-analysis reveals differences of immune profile between eutopic endometrium from stage I-II and III-IV endometriosis independently of hormonal milieu

Poli-Neto

Meola

Silva

et al. 2020

Sci Rep

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Eutopic endometrium appears to be crucial for endometriosis development. Despite of the evident importance, data regarding the cellular microenvironment remain unclear. Our objective was to explore the tissue microenvironment heterogeneity, transcripts, and pathways that are enriched in all phases of the menstrual cycle by analysing publicly deposited data derived from whole transcriptome microarrays of eutopic endometria of women with and without endometriosis. A meta-analysis of the transcriptome microarrays was performed using raw data available from a public database. Eligibility criteria included eutopic endometrium samples from women with endometriosis and healthy controls without any pathological condition reported the presence of an adequately reported normal menstrual phase, and samples containing both glandular and stromal components. Raw data were processed using a robust multiarray average method to provide background correction, normalisation, and summarisation. The batch effect was estimated by principal variant component analysis and removed using an empirical Bayes method. Cellular tissue heterogeneity was inferred using the xCell package. Differentially expressed genes were identified based on a 5% adjusted p value and a 2.0-fold change. Pathways were identified by functional enrichment based on the Molecular Signatures Database, a p value of < 5%, and an FDR q value of ≤ 25%. Genes that were more frequently found in pathways were identified using leading edge analysis. In a manner independent of cycle phase, the subpopulations of activated dendritic cells, CD4 T effector memory phenotype cells, eosinophils, macrophages M1, and natural killer T cells (NKT) were all higher in stage I-II endometriosis compared to those in healthy controls. The subpopulations of M2 macrophages and natural killer T cells were elevated in eutopic endometriums from women with stage III-IV endometriosis, and smooth muscle cells were always more prevalent in healthy eutopic endometriums. Among the differently expressed genes, FOS, FOSB, JUNB, and EGR1 were the most frequently mapped within the interaction networks, and this was independent of stage and cycle phase. The enriched pathways were directly related to immune surveillance, stem cell self-renewal, and epithelial mesenchymal transition. PI3K AKT mTOR, TGF signalling, and interferon alpha/gamma responses were enriched exclusively in stage III-IV endometriosis. The cellular microenvironments and immune cell profiles were different between eutopic endometriums from women with stage I-II and stage III-IV endometriosis, and these differences were independent of the hormonal milieu. Specifically, a pro-inflammatory profile was predominant in stage I-II endometriosis, and M1-M2 polarization into eutopic endometrium may be crucial for the progression of the disease. The higher prevalence of NKT cells in eutopic endometriums from women with endometriosis that

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“…Besides T cells, NK and NKT cells are known to have diverse functions in antitumor immune responses by directly killing malignant cells or induce cells such as CD8 + T cells to attack the tumor via the immune-activated production of cytokines [16,24]. Anti-PD1 monoclonal antibodies are designed to inhibit the inactivating binding of the programmed death-ligand 1 (PD-L1), by binding to the PD-1 receptor on the surface of an activated T cell, thus enabling the antitumor immune response by T cells [5].…”

Section: Discussionmentioning

confidence: 99%

Age-associated changes in the immune system may influence the response to anti-PD1 therapy in metastatic melanoma patients

Kasanen

Hernberg

Mäkelä

et al. 2020

Cancer Immunol Immunother

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Anti-PD1 treatment has improved the survival of metastatic melanoma patients, yet it is unknown which patients benefit from the treatment. In this exploratory study, we aimed to understand the effects of anti-PD1 therapy on the patients' immune system and discover the characteristics that would result in successful treatment. We collected peripheral blood (PB) samples from 17 immuno-oncology-naïve metastatic melanoma patients before and after 1 and 3 months of anti-PD1 therapy. In addition, matching tumor biopsies at the time of diagnosis were collected for tissue microarray. The complete blood counts, PB immunophenotype, serum cytokine profiles, and tumor-infiltrating lymphocytes were analyzed and correlated with the clinical data. Patients were categorized based on their disease control into responders (complete response, partial response, stable disease > 6 months, N = 11) and non-responders (progressive disease, stable disease ≤ 6 months, N = 6). During therapy, the PB natural killer T (NKT) cell frequency, expression of CD25 and CD45RO on cytotoxic natural killer (NK) cells, and serum CXC chemokine levels were significantly increased in responders. Furthermore, higher age together with age-associated characteristics from PB, lower frequency of PB-naïve CD8 + T cells, and elevated levels of serum MCP-4 and OPG were discovered as baseline predictors of treatment response. We therefore propose that in addition to T cells, anti-PD1 treatment is associated with NK-and NKT-cell population dynamics, and that the age-associated characteristics from PB together with older age may contribute to prolonged PFS in anti-PD1-treated melanoma patients.

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The Role of Natural Killer T Cells in Cancer—A Phenotypical and Functional Approach

Cited by 181 publications

References 270 publications

The Generation of CAR-Transfected Natural Killer T Cells for the Immunotherapy of Melanoma

The Generation of CAR-Transfected Natural Killer T Cells for the Immunotherapy of Melanoma

Transcriptome meta-analysis reveals differences of immune profile between eutopic endometrium from stage I-II and III-IV endometriosis independently of hormonal milieu

Age-associated changes in the immune system may influence the response to anti-PD1 therapy in metastatic melanoma patients

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