Helicobacter pylori enhances HLA-C expression in the human gastric adenocarcinoma cells AGS and can protect them from the cytotoxicity of natural killer cells.

Helicobacter pylori (H. pylori) seems to play causative roles in gastric cancers. H. pylori has also been detected in established gastric cancers. How the presence of H. pylori modulates immune response to the cancer is unclear. The cytotoxicity of natural killer (NK) cells, toward infected or malignant cells, is controlled by the repertoire of activating and inhibitory receptors expressed on their surface. Here, we studied H. pylori-induced changes in the expression of ligands, of activating and inhibitory receptors of NK cells, in the gastric adenocarcinoma AGS cells, and their impacts on NK cell responses. AGS cells lacked or had low surface expression of the class I major histocompatibility complex (MHC-I) molecules HLA-E and HLA-C-ligands of the major NK cell inhibitory receptors NKG2A and killer-cell Ig-like receptor (KIR), respectively. However, AGS cells had high surface expression of ligands of activating receptors DNAM-1 and CD2, and of the adhesion molecules LFA-1. Consistently, AGS cells were sensitive to killing by NK cells despite the expression of inhibitory KIR on NK cells. Furthermore, H. pylori enhanced HLA-C surface expression on AGS cells. H. pylori infection enhanced HLA-C protein synthesis, which could explain H. pylori-induced HLA-C surface expression. H. pylori infection enhanced HLA-C surface expression also in the hepatoma Huh7 and HepG2 cells. Furthermore, H. pylori-induced HLA-C surface expression on AGS cells promoted inhibition of NK cells by KIR, and thereby protected AGS cells from NK cell cytotoxicity. These results suggest that H. pylori enhances HLA-C expression in host cells and protects them from the cytotoxic attack of NK cells expressing HLA-C-specific inhibitory receptors.

Evaluating a combination treatment of NK cells and reovirus against bladder cancer cells using an in vitro assay to simulate intravesical therapy.

Intravesical treatment using either reovirus or natural killer (NK) cells serves as an efficient strategy for the treatment of bladder cancer cells (BCCs); however, corresponding monotherapies have often shown modest cytotoxicity. The potential of a locoregional combination using high-dose reovirus and NK cell therapy in an intravesical approach has not yet been studied. In this study, we evaluated the effectiveness of reoviruses and expanded NK cells (eNK) as potential strategies for the treatment of bladder cancer. The anti-tumor effects of mono-treatment with reovirus type 3 Dearing strain (RC402 and RP116) and in combination with interleukin (IL)-18/-21-pretreated eNK cells were investigated on BCC lines (5637, HT-1376, and 253J-BV) using intravesical therapy to simulate in vitro model. RP116 and IL-18/-21-pretreated eNK cells exhibited effective cytotoxicity against grade 1 carcinoma (5637 cells) when used alone, but not against HT-1376 (grade 2 carcinoma) and 253J-BV cells (derived from a metastatic site). Notably, combining RP116 with IL-18/-21-pretreated eNK cells displayed effective cytotoxicity against both HT-1376 and 253J-BV cells. Our findings underscore the potential of a combination therapy using reoviruses and NK cells as a promising strategy for treating bladder cancer.

CD8+ NKs as a potential biomarker of complete response and survival with lenalidomide plus R-GDP in the R2-GDP-GOTEL trial in recurrent/refractory diffuse large B cell lymphoma.

Background: Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. DLBCL is an aggressive disease that can be cured with upfront standard chemoimmunotherapy schedules. However, in approximately 35-40% of the patients DLBCL relapses, and therefore, especially in this setting, the search for new prognostic and predictive biomarkers is an urgent need. Natural killer (NK) are effector cells characterized by playing an important role in antitumor immunity due to their cytotoxic capacity and a subset of circulating NK that express CD8 have a higher cytotoxic function. In this substudy of the R2-GDP-GOTEL trial, we have evaluated blood CD8+ NK cells as a predictor of treatment response and survival in relapsed/refractory (R/R) DLBCL patients. Methods: 78 patients received the R2-GDP schedule in the phase II trial. Blood samples were analyzed by flow cytometry. Statistical analyses were carried out in order to identify the prognostic potential of CD8+ NKs at baseline in R/R DLBCL patients. Results: Our results showed that the number of circulating CD8+ NKs in R/R DLBCL patients were lower than in healthy donors, and it did not change during and after treatment. Nevertheless, the level of blood CD8+ NKs at baseline was associated with complete responses in patients with R/R DLBCL. In addition, we also demonstrated that CD8+ NKs levels have potential prognostic value in terms of overall survival in R/R DLBCL patients. Conclusion: CD8+ NKs represent a new biomarker with prediction and prognosis potential to be considered in the clinical management of patients with R/R DLBCL. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001620-29 EudraCT, ID:2014-001620-29.

Results of a phase I trial with Haploidentical mbIL-21 ex vivo expanded NK cells for patients with multiply relapsed and refractory AML.

Natural killer (NK)-cells have potent anti-tumor effects, yet it remains unclear if they are effective for patients with relapsed acute myeloid leukemia (AML). In a phase I clinical trial, we treated 12 patients (median age 60 years) with refractory AML (median 5 lines of prior therapy, median bone marrow blast count of 47%) with fludarabine/cytarabine followed by 6 infusions of NK-cells expanded from haploidentical donors using K562 feeder cells expressing membrane-bound IL21 and 4-1BBL. Patients received 106-107/kg/dose. No toxicity or graft-versus-host disease (GVHD) was observed and MTD was not reached. Seven patients (58.3%) responded and achieved a complete remission (CR) with/without count recovery. Median time to best response was 48 days. Five responding patients proceeded to a haploidentical transplant from the same donor. After a median follow-up of 52 months, 1-year overall survival (OS) for the entire group was 41.7%, better for patients who responded with CR/CRi (57.14%), and for patients who responded and underwent transplantation (60%). Persistence and expansion of donor-derived NK-cells were identified in patients' blood, and serum IFNγ levels rose concurrently with NK cell infusions. A higher count-functional inhibitory KIR was associated with higher likelihood of achieving CR/CRi. In conclusion, we observed a significant response to ex vivo expanded NK-cell administration in refractory AML patients without adverse effects.

Extranodal natural killer/T-cell lymphoma coexisting with peripheral T-cell lymphoma, not otherwise specified.

We report the case of a 52-year-old male who presented to our hospital with cervical lymphadenopathy. Lymph node biopsy revealed small atypical lymphoid cells positive for CD3 and CD5 and negative for CD56 and Epstein-Barr virus (EBV)-encoded small RNA (EBER) by in situ hybridization. CD4-positive cells and CD8-positive cells were mixed in almost equal numbers. He was diagnosed with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). The patient received one cycle of chemotherapy, resulting in severe sepsis. While undergoing treatment in the intensive care unit with an antimicrobial agent and prednisone, ascitic fluid appeared. Abdominal aspiration revealed neutrophil-predominant ascites and microbiological studies revealed Candida albicans. However, ascites did not improve when treated with micafungin for Candida peritonitis. Abdominal aspiration was re-performed, and atypical lymphoid cells that were positive for CD3 and CD56 were detected. EBV-DNA levels in whole blood were significantly elevated. Atypical lymphoid cells were positive for EBER by in situ hybridization and Southern blot analysis showed EBV terminal repeat monoclonal patterns. Bone marrow examination revealed the same atypical lymphoid cells. Therefore, the patient was diagnosed with extranodal natural killer/T-cell lymphoma (ENKTL) with bone marrow involvement 3 months after the diagnosis of PTCL-NOS. Complications associated with PTCL-NOS and ENKTL are rare. PTCL-NOS, chemotherapy, sepsis, and prednisone might have led to immunodeficiency and reactivation of EBV, which might be one of the pathophysiologies for developing ENKTL. Our case indicates that measuring EBV-DNA in the blood is a simple and prompt examination to detect complications of EBV-associated lymphoma.

Genomic features reveal potential benefit of adding anti-PD-1 immunotherapy to treat non-upper aerodigestive tract natural killer/T-cell lymphoma.

Natural killer/T-cell lymphoma (NKTCL) is a highly heterogeneous disease with a poor prognosis. However, the genomic characteristics and proper treatment strategies for non-upper aerodigestive tract NKTCL (NUAT-NKTCL), a rare subtype of NKTCL, remain largely unexplored. In this study, 1589 patients newly diagnosed with NKTCL at 14 hospitals were assessed, 196 (12.3%) of whom had NUAT-NKTCL with adverse clinical characteristics and an inferior prognosis. By using whole-genome sequencing (WGS) and whole-exome sequencing (WES) data, we found strikingly different mutation profiles between upper aerodigestive tract (UAT)- and NUAT-NKTCL patients, with the latter group exhibiting significantly higher genomic instability. In the NUAT-NKTCL cohort, 128 patients received frontline P-GEMOX chemotherapy, 37 of whom also received anti-PD-1 immunotherapy. The application of anti-PD-1 significantly improved progression-free survival (3-year PFS rate 53.9% versus 17.0%, P = 0.009) and overall survival (3-year OS rate 63.7% versus 29.2%, P = 0.01) in the matched NUAT-NKTCL cohort. WES revealed frequent mutations involving immune regulation and genomic instability in immunochemotherapy responders. Our study showed distinct clinical characteristics and mutational profiles in NUAT-NKTCL compared with UAT patients and suggested adding anti-PD-1 immunotherapy in front-line treatment of NUAT-NKTCL. Further studies are needed to validate the efficacy and related biomarkers for immunochemotherapy proposed in this study.

Increased Siglec-9/Siglec-9L interactions on NK cells predict poor HCC prognosis and present a targetable checkpoint for immunotherapy.

BACKGROUND & AIMS: Natural killer (NK) cell-based anti-hepatocellular carcinoma (HCC) therapy is an increasingly attractive approach that warrants further study. Siglec-9 interacts with its ligand (Siglec-9L) and restrains NK cell functions, suggesting it is a potential therapeutic target. However, in situ Siglec-9/Siglec-9L interactions in HCC have not been reported, and a relevant interventional strategy is lacking. Herein, we aim to illustrate Siglec-9/Siglec-9L-mediated cell sociology and identify small-molecule inhibitors targeting Siglec-9 that could improve the efficacy of NK cell-based immunotherapy for HCC. METHODS: Multiplexed immunofluorescence staining was performed to analyze the expression pattern of Siglec-7, -9 and their ligands in HCC tissues. Then we conducted docking-based virtual screening combined with bio-layer interferometry assays to identify a potent small-molecule Siglec-9 inhibitor. The therapeutic potential was further evaluated in vitro and in hepatoma-bearing NCG mice. RESULTS: Siglec-9 expression, rather than Siglec-7, was markedly upregulated on tumor-infiltrating NK cells, which correlated significantly with reduced survival of patients with HCC. Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival, further suggesting that Siglec-9/Siglec-9L interactions are a potential therapeutic target in HCC. In addition, we identified a small-molecule Siglec-9 inhibitor MTX-3937 which inhibited phosphorylation of Siglec-9 and downstream SHP1 and SHP2. Accordingly, MTX-3937 led to considerable improvement in NK cell function. Notably, MTX-3937 enhanced cytotoxicity of both human peripheral and tumor-infiltrating NK cells. Furthermore, transfer of MTX-3937-treated NK92 cells greatly suppressed the growth of hepatoma xenografts in NCG mice. CONCLUSIONS: Our study provides the rationale for HCC treatment by targeting Siglec-9 on NK cells and identifies a promising small-molecule inhibitor against Siglec-9 that enhances NK cell-mediated HCC surveillance. IMPACT AND IMPLICATIONS: Herein, we found that Siglec-9 expression is markedly upregulated on tumor-infiltrating natural killer (TINK) cells and correlates with reduced survival in patients with hepatocellular carcinoma (HCC). Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival. More importantly, we identified a small-molecule inhibitor targeting Siglec-9 that augments NK cell functions, revealing a novel immunotherapy strategy for liver cancer that warrants further clinical investigation.

Killing capacity analysis of tumor-infiltrating cytotoxic lymphocytes and impact on lymph node metastasis in differentiated papillary carcinoma of thyroid with the BRAF V600E mutation.

BACKGROUND: Cytotoxic lymphocytes (CLs) express potent toxins, including perforin (P) and granzyme-B (G), which brings about target cell death. The purpose of this study was to evaluate the killing capacity of tumor-infiltrating CLs by means of P and G analysis, and explore the association with lymph node metastasis in papillary carcinoma of thyroid (PTC) without Hashimoto's thyroiditis (HT). METHODS: Infiltration of lymphocytes in PTC was observed in frozen sections. Both fresh tumor tissues and paracancerous tissues with lymphocyte infiltration were collected and prepared into a single cell suspension. Flow cytometry was used to detect the percentages of CD3+P+, CD3+G+, CD8+P+, and CD8+G+ T lymphocytes (TLs) and CD16-CD56+P+ and CD16-CD56+G+ natural killer (NK) cells. Finally, we investigated differential expression of P and G in NK cells and cytotoxic T lymphocytes (CTLs) in paired tumor tissues (group T, n = 44) and paracancerous tissues (group N, n = 44) from patients with PTC with the BRAF V600E mutation. Furthermore, patients were divided into two groups according to whether cervical central lymph node metastasis (CCLNM) existed: group A (with lymph node metastases, n = 27) and group B (with nonlymph node metastases, n = 17). Patients were also divided into three groups according to the total number of positive CCLNM: group B, group C (with low-level lymph node metastases, less than 5, n = 17) and group D (with high-level lymph node metastases, no less than 5, n = 10). RESULTS: The percentage of CD3+P+ CTLs was significantly higher in group N than in group T (P < 0.05). The percentage of CD8+G+ CTLs was significantly higher in group T than in group N (P < 0.05). The percentages of CD3+G+, CD16-CD56+P+and CD16-CD56+G+ NK cells showed no significant difference in either group T or group N (P > 0.05). The percentages of CD3+P+ CTLs in group A and group C were significantly higher in the paracancerous tissue than in the tumor tissue (P < 0.05). The percentages of CD8+G+ CTLs in group A and group C were significantly higher in the tumor tissues than in the paracancerous tissues (P < 0.05). The percentage of CD16-CD56+G+ NK cells in group D was significantly higher in the tumor tissues than in the paracancerous tissues (P < 0.05). CONCLUSIONS: The killing capacity of infiltrating CLs in PTC differed between tumor tissues and paracancerous tissues. In cases with CCLNM, higher expression of CD16-CD56+G+ NK cells in tumor tissues may be associated with a high risk of lymph node metastasis.

Extranodal natural killer/T cell lymphoma nasal type simulating osteoradionecrosis with metachronic B lymphoma in the pelvis: Case report.

Extranodal Natural Killer/T Cell Lymphoma Nasal Type (EN-NK/T-CL-NT) is a non-Hodgkin extranodal lymphoma of unfavorable prognosis due to its aggressive nature. This neoplasm mainly affects the paranasal sinuses, nasopharynx, oropharynx, oral cavity, palate, and rarely intestinal, gastric and skin regions. 50-year-old female with a history of lymphoma in nasal and pelvic region. At four years of tumors-free, has facial asymmetry, accompanied by sub-palpebral, nasal and lip edema. Intraoral examination revealed a large ulceration suggestive of osteoradionecrosis. Gum biopsy shows Extranodal NK/T Cell Lymphoma Nasal Type (EN-NK/T-CL-NT). In this case we highlight the characteristics of EN-NK/T-CL-NT with a presentation of osteoradionecrosis-like. Unfortunately, the nature of this tumor led to the patient's death. Clinical follow-up of patients with cancer is imperative to mend and/or decrease treatment complications, as well as to identify second primary tumors or the spread of the underlying disease.

EBV-positive Nodal T-Cell and NK-Cell Lymphoma: A Study of 26 Cases Including a Subset With Strong CD30 Expression Mimicking Anaplastic Large Cell Lymphoma.

Epstein-Barr virus (EBV)-positive nodal T-cell and NK-cell lymphoma is a rare neoplasm of cytotoxic T-cell or NK-cell lineage. Here, we report 26 cases affecting 14 men and 12 women with a median age of 52 years. All patients presented with disease involving multiple lymph nodes, and 20 of 22 (91%) fully staged patients had advanced Ann Arbor stage disease. Spleen, liver, and bone marrow were involved in 70%, 50%, and 52% of cases, respectively. These patients had a dismal prognosis with a median survival of 30 days. Histologically, lymph nodes were replaced by lymphoma in a diffuse pattern. Lymphoma cells were variable in size and large cell morphology was seen in 62% of cases. The neoplastic cells were CD4-/CD8- in 14 (54%) cases and CD4-/CD8+ in 12 (46%) cases. CD56 was positive in 14 (54%) cases. CD30 was positive in 20 (77%) cases; a strong and diffuse pattern was observed in 14 (54%) cases, mimicking, in part, anaplastic large cell lymphoma (ALCL). CD30 expression was associated with younger age and large cell morphology. In summary, EBV+ nodal T-cell and NK-cell lymphoma is an aggressive disease with a poor prognosis. These neoplasms are heterogeneous at the morphologic and immunophenotypic levels. Diffuse and strong expression of CD30 could potentially lead to a misdiagnosis of ALCL if EBV evaluation is not performed. Distinguishing between EBV+ nodal T-cell and NK-cell lymphoma from ALCL is important because treatment strategy and prognosis differ. CD30 expression offers a potential therapeutic target for patients with this aggressive disease.

Distinct peripheral T-cell and NK-cell profiles in HGBL-MYC/BCL2 vs patients with DLBCL NOS.

ABSTRACT: Patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBL-MYC/BCL2) respond poorly to immunochemotherapy compared with patients with diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) without a MYC rearrangement. This suggests a negative impact of lymphoma-intrinsic MYC on the immune system. To investigate this, we compared circulating T cells and natural killer (NK) cells of patients with HGBL-MYC/BCL2 (n = 66), patients with DLBCL NOS (n = 53), and age-matched healthy donors (HDs; n = 16) by flow cytometry and performed proliferation, cytokine production, and cytotoxicity assays. Compared with HDs, both lymphoma subtypes displayed similar frequencies of CD8+ T cells but decreased CD4+ T cells. Regulatory T-cell (Treg) frequencies were reduced only in patients with DLBCL NOS. Activated (HLA-DR+/CD38+) T cells, PD-1+CD4+ T cells, and PD-1+Tregs were increased in both lymphoma subtypes, but PD-1+CD8+ T cells were increased only in HGBL-MYC/BCL2. Patients with DLBCL NOS, but not patients with HGBL-MYC/BCL2, exhibited higher frequencies of senescent T cells than HDs. Functional assays showed no overt differences between both lymphoma groups and HDs. Deeper analyses revealed that PD-1+ T cells of patients with HGBL-MYC/BCL2 were exhausted with impaired cytokine production and degranulation. Patients with DLBCL NOS, but not patients with HGBL-MYC/BCL2, exhibited higher frequencies of NK cells expressing inhibiting receptor NKG2A. Both lymphoma subtypes exhibited lower TIM-3+- and DNAM-1+-expressing NK cells. Although NK cells of patients with HGBL-MYC/BCL2 showed less degranulation, they were not defective in cytotoxicity. In conclusion, our results demonstrate an increased exhaustion in circulating T cells of patients with HGBL-MYC/BCL2. Nonetheless, the overall intact peripheral T-cell and NK-cell functions in these patients emphasize the importance of investigating potential immune evasion in the microenvironment of MYC-rearranged lymphomas.

Elevated serum IL-6 and total IgEAb are associated with poor survival in natural killer/T-cell lymphoma.

Natural killer/T-cell lymphoma (NKTCL) is an aggressive and malignant condition with a high mortality rate. Prognostic factors may assist to evaluate the outcome of the disease and may also be useful in selecting appropriate therapeutic strategies for patients. The study aims to describe NKTCL in terms of its clinical features, laboratory examinations, and immunophenotypes and to analyze relevance affecting patient survival outcomes. The patients diagnosed as NKTCL in Jinling Hospital from Jan. 2012 to Dec. 2022 were reviewed retrospectively in this study basing on histopathology. The analysis was performed to evaluate overall survival (OS). A total of 125 NKTCL patients were included, which mainly affected male more than female with the onset median age of 51.00 years old (range, 14 ~ 85 y). NKTCL commonly affects the nasopharynx and upper aerodigestive tract, intestines, and skin. The median overall survival was 13.00 months (range, 2-156 m), and the 5-year survival rate was 9.8%. Under univariable analysis revealed the following factors at diagnosis age: serum total IgEAb ≥ 54.6 IU/mL, IL-6 ≥ 32.445 ng/L, elevated PINK score, smoking, and extranasopharyngeal site were statistically significant predictors for OS. Compared to the patients who received radiotherapy alone or chemotherapy alone, the patients who received combined chemoradiotherapy had longer OS. We found that IL-6 and total IgEAb were significant prognostic factors in NKTCL patients. Also, extranasopharyngeal site was correlated with advanced disease.

Natural killer cells at the forefront of cancer immunotherapy with immune potency, genetic engineering, and nanotechnology.

Natural killer (NK) cells are vital components of the human immune system, acting as innate lymphocytes and playing a crucial role in immune surveillance. Their unique ability to independently eliminate target cells without antigen contact or antibodies has sparked interest in immunological research. This review examines recent NK cell developments and applications, encompassing immune functions, interactions with target cells, genetic engineering techniques, pharmaceutical interventions, and implications in cancers. Insights into NK cell regulation emerge, with a focus on promising genetic engineering like CAR-engineered NK cells, enhancing specificity against tumors. Immune checkpoint inhibitors also enhance NK cells' potential in cancer therapy. Nanotechnology's emergence as a tool for targeted drug delivery to improve NK cell therapies is explored. In conclusion, NK cells are pivotal in immunity, holding exciting potential in cancer immunotherapy. Ongoing research promises novel therapeutic strategies, advancing immunotherapy and medical interventions.

Lymphocyte subsets and soluble forms of MIC-A and MIC-B are prognostic factors in non-Hodgkin lymphoma patients.

MIC-A and MIC-B are the natural ligands for NKG2D, an activator receptor expressed in NK cells. Soluble isoforms of MIC-A and MIC-B (sMICA, sMICB) have been identified in different malignancies, affecting NK cells' cytotoxicity. The study was performed to determine the levels of sMICA, sMICB, the expression of MIC-A, and MIC-B on tumor tissues, and lymphocyte subpopulations (CD4 + , CD8 + , NK, NKT, Tγδ cells, B cells, monocytes) in 94 patients with non-Hodgkin's lymphoma (NHL) and 72 healthy donors.The most frequent lymphoma was diffuse large B cell lymphoma (48%). Patients with NHL had decreased numbers of CD4 T cells, CD8 T cells, B cells, monocytes, NK cells, type 1 dendritic cells, γδ T cells, and increased iNKT cells. Patients showed higher levels of sMIC-A and similar serum levels of sMIC-B.Survival was poorer in patients having higher LDH values and lower numbers of CD4 T cells, type 1 dendritic cells, gamma-delta T cells, and high levels of sMIC-A.In conclusion, high levels of sMIC and decreased numbers in circulating lymphocyte subsets are related to poor outcomes in NHL.

Poliovirus receptor-based chimeric antigen receptor T cells combined with NK-92 cells exert potent activity against glioblastoma.

BACKGROUND: Poliovirus receptor interacts with 3 receptors: T-cell immunoglobulin immunoreceptor tyrosine-based inhibitory motif, CD96, and DNAX accessory molecule 1, which are predominantly expressed on T cells and natural killer (NK) cells. Many solid tumors, including IDH wild-type glioblastoma, have been reported to overexpress poliovirus receptor, and this overexpression is associated with poor prognosis. However, there are no preclinical or clinical trials investigating the use of cell-based immunotherapies targeting poliovirus receptor in IDH wild-type glioblastoma. METHODS: We analyzed poliovirus receptor expression in transcriptome sequencing databases and specimens from IDH wild-type glioblastoma patients. We developed poliovirus receptor targeting chimeric antigen receptor T cells using lentivirus. The antitumor activity of chimeric antigen receptor T cells was demonstrated in patient-derived glioma stem cells, intracranial and subcutaneous mouse xenograft models. RESULTS: We verified poliovirus receptor expression in primary glioma stem cells, surgical specimens from IDH wild-type glioblastoma patients, and organoids. Accordingly, we developed poliovirus receptor-based second-generation chimeric antigen receptor T cells. The antitumor activity of chimeric antigen receptor T cells was demonstrated in glioma stem cells and xenograft models. Tumor recurrence occurred in intracranial xenograft models because of antigen loss. The combinational therapy of tyrosine-based inhibitory motif extracellular domain-based chimeric antigen receptor T cells and NK-92 cells markedly suppressed tumor recurrence and prolonged survival. CONCLUSIONS: Poliovirus receptor-based chimeric antigen receptor T cells were capable of killing glioma stem cells and suppressing tumor recurrence when combined with NK-92 cells.

Identification of SGMS2 as a molecule involved in natural killer cell recruitment and its in-deep analysis in the liver cancer microenvironment: Evidence from large populations cohort.

BACKGROUND: Liver cancer, a common malignancy within the digestive system, presents with a particularly grim prognosis. Within the immune microenvironment, the role of natural killer (NK) cells in liver cancer remains unclear. METHODS: We sourced data on clinical parameters and gene expressions for liver cancer patients from The Cancer Genome Atlas Program database and carried out all analyses using R software and its relevant codes. RESULTS: In our research, we delved into the genes intertwined with NK cells in hepatocellular carcinoma (HCC). Leveraging the QUANTISEQ and MCPCOUNTER algorithms to quantify NK cells, we spotlighted genes vital to the recruitment of NK cells. Among these genes, GDE1, WDFY3, DNAJB14, PKD2, DGAT2, SGMS2 and MKNK2 showed a strong correlation with patient outcomes. We also mapped out the single-cell expression trajectories of these genes within the HCC milieu. From our findings, SGMS2 emerged as a key gene warranting further scrutiny. Our in-depth analysis of SGMS2 shed light on its influence over specific biological pathways, its contribution to the immune landscape and its role in genomic instability within HCC. Drawing from this, we formulated a predictive model rooted in SGMS2-associated genes. This model showcased remarkable precision across both training and validation cohorts. CONCLUSIONS: Overall, our investigation underscored the profound implications of SGMS2, a gene pivotal to NK cell infiltration, in the landscape of HCC, thereby positioning it as a potential linchpin in oncological strategies.

Clinical features, prognostic stratification, and treatment of advanced-stage non-nasal type extranodal natural killer/T-cell lymphoma: a multi-institutional real-world study.

The present study aimed to investigate the clinical features, prognosis, and treatment of advanced-stage non-nasal type extranodal natural killer/T-cell lymphoma (ENKTCL). This real-world study retrospectively reviewed 56 newly diagnosed advanced-stage non-nasal type ENKTCL patients from two large-scale Chinese cancer centers in the last 10-15 years and screened 139 newly diagnosed advanced-stage nasal type ENKTCLs admitted during the same period for comparison. The non-nasal type ENKTCLs exhibited significantly higher Ki-67 expression levels compared to nasal type disease (P = 0.011). With a median follow-up duration of 75.03 months, the non-nasal group showed slightly inferior survival outcomes without statistically significant differences compared to the nasal group (median overall survival (OS): 14.57 vs. 21.53 months, 5-year OS: 28.0% vs. 38.5%, P = 0.120). Eastern Cooperative Oncology Group (ECOG) score ≥ 2 (hazard ratio (HR) = 2.18, P = 0.039) and lactic dehydrogenase (LDH) elevation (HR = 2.44, P = 0.012) were significantly correlated with worse OS in the non-nasal group. First-line gemcitabine-based chemotherapy regimens showed a trend toward slightly improved efficacy and survival outcomes compared to non-gemcitabine-based ones in the present cohort of non-nasal ENKTCLs (objective response rate: 91.7% vs. 63.6%, P = 0.144; complete response rate: 50.0% vs. 33.3%, P = 0.502; median progression-free survival: 10.43 vs. 3.40 months, P = 0.106; median OS: 25.13 vs. 9.30 months, P = 0.125), which requires further validation in larger sample size studies. Advanced-stage non-nasal type patients could achieve comparable prognosis with nasal cases after rational therapy. The modified nomogram-revised index (including age, ECOG score, and LDH) and modified international prognostic index (including age, ECOG score, LDH, and number of extranodal involvement) functioned effectively for prognostic stratification in non-nasal type ENKTCLs.