Up-regulation of DNAM-1 and NKp30, associated with improvement of NK cells activation after long-term culture of mononuclear cells from patients with ovarian neoplasia

Silva, Rodrigo Fernandes da; Petta, Carlos Alberto; Derchain, Sophie; Alici, Evren; Guimarães, Fernando

doi:10.1016/j.humimm.2014.05.010

Cited by 10 publications

(12 citation statements)

References 37 publications

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“…This is consistent with the high level of degranulation of NK cells from ASC group, and suggests a previous stimulation of NK cells in the tumor site. This observation is also in agreement with our previous study which showed that continuous in vitro stimulation with IL-2 continuously increases NK activation [38]. Elevated TNF-α levels observed in ascites with EOC cells suggests an inflammatory process that possibly benefits tumor development.…”

Section: Discussionsupporting

confidence: 92%

“…The importance of the activating receptors for NK antitumor functions has been demonstrated in patients with ovarian cancer [38,39,40]. As mentioned before, NK cell cytolytic activity is dependent on inhibitory and activating signals resulting from the interaction of their receptors with their respective ligands on target cells.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have shown that the antitumor function of NK cells from peripheral blood of patients with ovarian cancer can be significantly augmented by in vitro stimulation with recombinant IL-2 [31,32], and that primary malignant ovarian cells are susceptible to killing by allogeneic NK lymphocytes. However, autologous NK cells do not display significant cytotoxicity in vitro [37,38]. These observations suggest a functional impairment of NK cells in patients who suffer from ovarian cancer, possibly due to the exposure of NK cells to ovarian cancer cells and/or elements present in the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

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Natural Killer Cells Response to IL-2 Stimulation Is Distinct between Ascites with the Presence or Absence of Malignant Cells in Ovarian Cancer Patients

Silva

Yoshida

Cardozo

et al. 2017

IJMS

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Peritoneal ascites are a distinguishable feature of patients with advanced epithelial ovarian cancer (EOC). The presence of different lymphocyte subsets has been reported in EOC-associated ascites, which also can or not contain malignant cells. The goal of this study was to analyze the functional characteristics of natural killer (NK) cells from EOC-associated ascites in terms of their expression of activating receptors and ascites’ contents of lymphocyte subtypes, cytokine profile and presence of EOC cells. NK cell function was evaluated by the expression of the degranulation marker CD107a in resting and interleukin (IL)-2 stimulated NK cells from ascites and blood. Degranulation of NK cells from EOC cell-free ascites was significantly (p < 0.05) higher than all the other groups, either in their resting state or after IL-2 stimulation, suggesting a previous local stimulation. In contrast, treatment with IL-2 had no effect on NK cells from ascites with EOC cells. The amount of regulatory T cells was significantly higher in ascites with EOC cells compared to EOC cell-free ascites. Ascites with EOC cells also had higher levels of tumor necrosis factor (TNF)-α, suggesting inflammation related to the malignancy. In conclusion, the functional performance of NK cells was distinct between EOC cell-free ascites and ascites with EOC cells. The impairment of NK cell response to IL-2 in ascites with EOC cells was consistent with an immunosuppressive tumor microenvironment.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Natural Killer Cells Response to IL-2 Stimulation Is Distinct between Ascites with the Presence or Absence of Malignant Cells in Ovarian Cancer Patients

Silva

Yoshida

Cardozo

et al. 2017

IJMS

Self Cite

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“…However, tumors were able to reset the upmodulated ratios of CD226/iKIR receptors induced by licensing interactions to escape the cytolytic activity of NKcs. In our cohort, this was clearly demonstrated in terminally ill patients with high tumor burdens and has previously been described in patients with ovarian cancer and AML (45,46). Furthermore, our data indicate that the ratios of CD226/iKIR receptors set on NKcs by licensing interactions are a dynamic event that depends on the input signals that NKcs receive in each scenario, as previously suggested (21).…”

Section: Discussionsupporting

confidence: 87%

NK Cell Education in Tumor Immune Surveillance: DNAM-1/KIR Receptor Ratios as Predictive Biomarkers for Solid Tumor Outcome

Guillamón

Martínez‐Sánchez

Gimeno

et al. 2018

Cancer Immunology Research

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Natural killer cell (NKc)-based therapies offer promising outcomes in patients with tumors, but they could improve with appropriate selection of donors and optimization of methods to expand NKcs in vitro. Education through licensing interactions of inhibitory killer cell immunoglobulin-like receptors (iKIR) and NKG2A with their cognate HLA class-I ligands optimizes NKc functional competence. This work has evaluated the role of licensing interactions in NKc differentiation and the survival of cancer patients. We have analyzed KIR and KIR-ligand genes, and the expression of activating (CD16 and DNAM-1/CD226) and inhibitory (NKG2A and iKIRs) receptors on peripheral blood NKcs in 621 healthy controls and 249 solid cancer patients (80 melanoma, 80 bladder, and 89 ovarian). Licensing interactions upregulated the expression of activating CD226, reduced that of iKIR receptors, and shifted the CD226/iKIR receptor ratio on NKc membranes to activating receptors. A high tumor burden decreased CD226 expression, reduced the ratio of CD226/iKIR, and negatively affected patient survival. The progression-free survival (38.1 vs. 67.0 months, P < 0.002) and overall survival (56.3 vs. 99.6 months, P < 0.00001) were significantly shorter in patients with lower expression of CD226 on NKcs. Hence, transformed cells can downmodulate these licensing-driven receptor rearrangements as a specific mechanism to escape NKc immune surveillance. Our results suggest the importance of the CD226/ iKIR receptor ratio of NKcs induced by licensing interactions as critical determinants for solid cancer immune surveillance, and may provide predictive biomarkers for patient survival that may also improve the selection of donors for NKc immunotherapy. Cancer Immunol Res; 6(12); 1537-47. Ó2018 AACR. NKcs can also express up to 6 different activating KIR (aKIRs): KIR2DS1-5 and KIR3DS1. Only the interactions between KIR2DS1/HLA-C2 allotypes (15, 16), KIR2DS4/HLA-A Ã 1102, and to a limited number of HLA-C1/-C2 alleles and KIR3DS1 Ã 014/HLA-Bw4 (17-19) have been reported, although

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“…CD104 [integrin beta 4 (ITGB4)] mediates cell-matrix or cell-cell adhesion, enhances cell growth and signaling, and thus plays a pivotal role in cancer invasion [26]. CD107a (lysosome-associated membrane glycoprotein 1), higher expressed in metastatic ovarian neoplasia, correlates with the metastatic potential [27]. CD121a (IL-1 receptor, type I) activates PIK3R1 and MYD88.…”

Section: Resultsmentioning

confidence: 99%

A rational approach for cancer stem-like cell isolation and characterization using CD44 and prominin-1(CD133) as selection markers

Lee

et al. 2016

Oncotarget

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The availability of adequate cancer stem cells or cancer stem-like cell (CSC) is important in cancer study. From ovarian cancer cell lines, SKOV3 and OVCAR3, we induced peritoneal ascites tumors in immunodeficient mice. Among the cells (SKOV3.PX1 and OVCAR3.PX1) from those tumors, we sorted both CD44 and CD133 positive cells (SKOV3.PX1_133+44+, OVCAR3.PX1_133+44+), which manifest the characteristics of self-renewal, multi-lineage differentiation, chemoresistance and tumorigenicity, those of cancer stem-like cells (CSLC). Intraperitoneal transplantation of these CD44 and CD133 positive cells resulted in poorer survival in the engrafted animals. Clinically, increased CD133 expression was found in moderately and poorly differentiated (grade II and III) ovarian serous cystadenocarcinomas. The ascites tumor cells from human ovarian cancers demonstrated more CD133 and CD44 expressions than those from primary ovarian or metastatic tumors and confer tumorigenicity in immunodeficient mice. Compared to their parental cells, the SKOV3.PX1_133+44+ and OVCAR3.PX1_133+44+ cells uniquely expressed 5 CD markers (CD97, CD104, CD107a, CD121a, and CD125). Among these markers, CD97, CD104, CD107a, and CD121a are significantly more expressed in the CD133+ and CD44+ double positive cells of human ovarian ascites tumor cells (Ascites_133+44+) than those from primary ovarian or metastatic tumors. The cancer stem-like cells were enriched from 3% to more than 70% after this manipulation. This intraperitoneal enrichment of cancer stem-like cells, from ovarian cancer cell lines or primary ovarian tumor, potentially provides an adequate amount of ovarian cancer stem-like cells for the ovarian cancer study and possibly benefits cancer therapy.

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Up-regulation of DNAM-1 and NKp30, associated with improvement of NK cells activation after long-term culture of mononuclear cells from patients with ovarian neoplasia

Cited by 10 publications

References 37 publications

Natural Killer Cells Response to IL-2 Stimulation Is Distinct between Ascites with the Presence or Absence of Malignant Cells in Ovarian Cancer Patients

Natural Killer Cells Response to IL-2 Stimulation Is Distinct between Ascites with the Presence or Absence of Malignant Cells in Ovarian Cancer Patients

NK Cell Education in Tumor Immune Surveillance: DNAM-1/KIR Receptor Ratios as Predictive Biomarkers for Solid Tumor Outcome

A rational approach for cancer stem-like cell isolation and characterization using CD44 and prominin-1(CD133) as selection markers

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