Increased expression of adenosine A3 receptor in tumor-infiltrating natural killer cells.
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ABSTRACT:
SUBMITTER: Bi J
PROVIDER: S-EPMC8027170 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The functional diversity of natural killer (NK) cell repertoires stems from differentiation, homeostatic, receptor-ligand interactions and adaptive-like responses to viral infections. In the present study, we generated a single-cell transcriptional reference map of healthy human blood- and tissue-derived NK cells, with temporal resolution and fate-specific expression of gene-regulatory networks defining NK cell differentiation. Transfer learning facilitated incorporation of tumor-infiltrating NK cell transcriptomes (39 datasets, 7 solid tumors, 427 patients) into the reference map to analyze tumor microenvironment (TME)-induced perturbations. Of the six functionally distinct NK cell states identified, a dysfunctional stressed CD56bright state susceptible to TME-induced immunosuppression and a cytotoxic TME-resistant effector CD56dim state were commonly enriched across tumor types, the ratio of which was predictive of patient outcome in malignant melanoma and osteosarcoma. This resource may inform the design of new NK cell therapies and can be extended through transfer learning to interrogate new datasets from experimental perturbations or disease conditions.
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Project description:Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This "polarization" has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as "TINKs") and tumor-associated NK (altered peripheral NK cells, which here we call "TANKs") are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology.
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Project description:Tumor-infiltrating lymphocytes play an essential role in improving clinical outcome of neuroblastoma (NB) patients, but their relationship with other tumor-infiltrating immune cells in the T cell-inflamed tumors remains poorly investigated. Here we show that dendritic cells (DCs) and natural killer (NK) cells are positively correlated with T-cell infiltration in human NB, both at transcriptional and protein levels, and associate with a favorable prognosis. Multiplex imaging displays DC/NK/T cell conjugates in the tumor microenvironment of low-risk NB. Remarkably, this connection is further strengthened by the identification of gene signatures related to DCs and NK cells able to predict survival of NB patients and strongly correlate with the expression of PD-1 and PD-L1. In summary, our findings unveil a key prognostic role of DCs and NK cells and indicate their related gene signatures as promising tools for the identification of clinical biomarkers to better define risk stratification and survival of NB patients.
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Project description:Natural killer (NK) cells are innate immune effector cells that play a crucial role in immune surveillance and the destruction of cancer cells. NK cells express a low-affinity receptor for the Fc or constant region of immunoglobulin G (FcγRIIIa) and multiple cytokine receptors that respond to antibody-coated targets and cytokines in the tumor microenvironment. In the present work, microarray gene expression analysis revealed that the IL-21 receptor (IL-21R) was strongly upregulated following FcR stimulation. The IL-21R was found to be upregulated on FcR-stimulated NK cells at the transcript level as determined by reverse transcription polymerase chain reaction (RT-PCR). Immunoblot analysis revealed that protein expression of the IL-21R peaked at 8 h post-stimulation of the FcR. Inhibition of the mitogen-activated protein kinase (MAPK) pathway downstream of the FcR blocked the induction of IL-21R expression. Increased expression of the IL-21R sensitized NK cells to IL-21 stimulation, as treatment of FcR-stimulated NK cells led to significantly increased phosphorylation of STAT1 and STAT3, as measured by intracellular flow cytometry and immunoblot analysis. Following FcR-stimulation, IL-21-activated NK cells were better able to mediate the lysis of trastuzumab-coated human epidermal growth factor receptor 2 (HER2+) SK-BR-3 tumor cells as compared to control-treated cells. Likewise, IL-21-induced NK cell secretion of IFNγ following exposure to antibody-coated tumor cells was enhanced following FcR-stimulation. The analysis of NK cells from patients receiving trastuzumab therapy for HER2+ cancer exhibited increased levels of the IL-21R following the administration of antibody suggesting that the presence of monoclonal antibody-coated tumor cells in vivo can stimulate the increased expression of IL-21R on NK cells.
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Project description:Background: Tumor-infiltrating natural killer (NK) cells (TINKs) are crucial immune cells in tumor defense, and might be related to tumor prognosis. However, the results were discrepant among different studies. The present meta-analysis was performed to comprehensively assess the prognostic value of NK cell markers in solid tumor tissues. Methods: PubMed, Web of Science, and EMBASE were searched to identify original researches reporting the prognostic significance of TINKs in solid tumors. NK cell markers CD56, CD57, NKp30, and NKp46 were included in the analysis. The hazard ratios (HRs) and 95% confidence intervals (CIs) of pooled overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS), progression-free survival (PFS), and recurrence-free survival (RFS) were calculated by STATA software 14.0 to assess the prognostic significance. Results : Of the 56 included studies, there were 18 studies on CD56, 31 studies on CD57, 1 study on NKp30, and 7 studies on NKp46. High levels of CD56, CD57, NKp30, and NKp46 were significantly correlated with better OS of patients with solid malignancies (HR = 0.473, 95%CI: 0.315-0.710, p < 0.001; HR = 0.484, 95%CI: 0.380-0.616, p < 0.001; HR = 0.34, 95%CI: 0.14-0.80, p = 0.014; HR = 0.622, 95%CI: 0.470-0.821, p < 0.001, respectively). Our results also revealed that CD56, CD57, and NKp46 could act as independent prognostic predictors for favorable OS (HR = 0.372, 95%CI: 0.261-0.531, p < 0.001; HR = 0.525, 95%CI: 0.346-0.797, p = 0.003; HR = 0.559, 95%CI: 0.385-0.812, p = 0.002, respectively). Conclusions : Our results indicated that high levels of NK cell markers in solid tumor tissues could predict favorable prognosis for solid tumor patients.
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Project description:Infiltrating immune cells play a central role in degenerative joint disease associated with osteoarthritis (OA) and particle-mediated periprosthetic osteolysis. The goal of this study was to characterize a newly identified population of synovial tissue-infiltrating natural killer (NK) cells obtained from patients with OA or patients with periprosthetic joint inflammation.Synovial and interfacial tissue samples were collected from patients with OA who were undergoing primary or revision total joint replacement (TJR) surgery. The histologic features of OA synovium obtained from patients undergoing primary surgery and interfacial tissue obtained from patients undergoing revision surgery were determined by immunohistochemistry and immunofluorescence. Synovial tissue-infiltrating NK cells were evaluated for the expression of surface receptors, using flow cytometry. Chemoattractant and cytokine protein and RNA levels in synovial and interfacial tissue and fluid were assessed by Luminex assay and real-time quantitative polymerase chain reaction. Cytokine production and degranulation by stimulated synovial tissue versus normal blood NK cells were evaluated by intracellular cytokine staining.NK cells comprised nearly 30% of the CD45+ mononuclear cell infiltrate in synovial tissue obtained from patients undergoing primary TJR and from patients undergoing revision TJR. NK cells from both groups expressed CXCR3, CCR5, L-selectin, ?4 integrins, and cutaneous lymphocyte antigen. Synovial fluid from patients undergoing revision surgery contained elevated concentrations of the NK cell attractants CCL4, CCL5, CXCL9, and CXCL10; all levels in synovial fluid obtained from patients undergoing revision surgery were higher than those in synovial fluid from patients undergoing primary surgery. Cytokine-stimulated interferon-? production was significantly impaired in NK cells derived from primary and revision TJRs compared with blood NK cells.NK cells are a principal tissue-infiltrating lymphocyte subset in patients with OA and patients with periprosthetic inflammation and display a quiescent phenotype that is consistent with postactivation exhaustion.
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Project description:Natural killer (NK) cells serve a critical role in the immune response against microbes and developing tumors. We have demonstrated that NK cells produce stimulatory cytokines (e.g., IFN-γ) in response to potent stimulation via immobilized IgG (to engage Fc receptors) and interleukin (IL)-12. CD25 is a component of the high-affinity IL-2R, which promotes NK cell activation in response to low doses of IL-2 such as those released by activated T cells. We hypothesized that stimulation of NK cells via IgG and IL-12 would enhance CD25 expression and promote NK cell anti-tumor activity in response to low-dose IL-2. It was confirmed that this dual stimulation strategy significantly enhanced NK cell CD25 expression compared to unstimulated cells or cells treated with IgG or IL-12 alone. Dual stimulated NK cells also were more responsive to low-dose IL-2. Dual stimulated NK cells subsequently treated with low-dose IL-2 (10 pg/mL) displayed enhanced intracellular signaling as indicated by increased pSTAT5 levels. IFN-γ production and cytotoxicity against K562 cells by NK cells stimulated with low-dose IL-2 was comparable to that of cells treated with high-dose IL-2 (10 ng/mL). Importantly, cells isolated from head and neck cancer patients receiving the mAb cetuximab and IL-12 on a clinical trial displayed increased CD25 expression following combination therapy compared to baseline. Altogether, these findings suggest that FcR and IL-12R co-stimulation induces expression of the high-affinity IL-2R and promotes NK cell anti-tumor activity.
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Project description:Natural killer (NK) cells are important innate cytotoxic lymphocytes with a rapid and efficient capacity to recognize and kill tumor cells. In recent years, adoptive transfer of autologous- or allogeneic-activated NK cells has become a promising cellular therapy for cancer. However, the therapeutic efficiency is encouraging in hematopoietic malignancies, but disappointing in solid tumors, for which the use of NK-cell-based therapies presents considerable challenges. It is difficult for NK cells to traffic to, and infiltrate into, tumor sites. NK cell function, phenotype, activation, and persistence are impaired by the tumor microenvironment, even leading to NK cell dysfunction or exhaustion. Many strategies focusing on improving NK cells' durable persistence, activation, and cytolytic activity, including activation with cytokines or analogs, have been attempted. Modifying them with chimeric antigen receptors further increases the targeting specificity of NK cells. Checkpoint blockades can relieve the exhausted state of NK cells. In this review, we discuss how the cytolytic and effector functions of NK cells are affected by the tumor microenvironment and summarize the various immunotherapeutic strategies based on NK cells. In particular, we discuss recent advances in overcoming the suppressive effect of the tumor microenvironment with the aim of enhancing the clinical outcome in solid tumors treated with NK-cell-based immunotherapy.
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