There are no effective treatment options for patients with poor performance status and limited liver reserve, classified as Child-Pugh Grade B and C. A 61-year-old man with a prior medical history of hepatitis C virus infection was admitted to the hospital with abdominal distension and significant abdominal ascites. He was diagnosed with stage IVB hepatocellular carcinoma (HCC), characterized by multiple metastases to lymph nodes, lungs, and bones. After receiving combined immune therapy, including dendritic cell therapy targeting WT1 and α-Galactosylceramide, natural killer cells, and Nivolumab, the patient showed significant improvement in HCC and liver reserve function and followed standard treatment. Combined immune therapy is potentially an important option for patients with advanced hepatocellular carcinoma and poor liver reserve function, especially for relatively young patients.

Cholangiocarcinoma (CCA) is a rare disease characterized by malignant cells derived from the epithelial cells of the biliary duct system. Despite extensive treatments, the prognosis for CCA remains poor, emphasizing the critical need for the development of novel treatments. Considerable attention has been directed towards innate immune effector cells, which can recognize tumor cells independently of the major histocompatibility complex, laying the foundation for the development of off-the-shelf drugs. In this study, we cultured innate immune cells obtained from the peripheral blood of healthy adults and conducted a comparative analysis of the effector functions against CCA cell lines by Vδ2 γδ T cells and NK cells. This analysis was performed using standard short- and long-term cytotoxicity assays, as well as ELISA for IFN-γ. Vδ2 γδ T cells demonstrated cytotoxicity and IFN-γ production in response to CCA cells in a TCR-dependent manner, particularly in the presence of tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate, a bisphosphonate prodrug. In contrast, direct killing and antibody-dependent cellular cytotoxicity were relatively slow and weak. Conversely, NK cells displayed potent, direct cytotoxicity against CCA cells. In summary, both Vδ2 γδ T cells and NK cells show promise as innate immune effector cells for adoptive transfer therapy in the context of CCA.

UNASSIGNED: Peripheral blood stem cell (PBSC) donation is the primary procedure used to collect hematopoietic stem and progenitor cells (HSPCs) for hematopoietic stem cell transplantation. Single bouts of exercise transiently enrich peripheral blood with HSPCs and cytolytic natural killer cells (CD56dim), which are important in preventing post-transplant complications. To provide a rationale to investigate the utility of exercise in a PBSC donation setting (≈3 h), this study aimed to establish whether interval cycling increased peripheral blood HSPC and CD56dim concentrations to a greater degree than continuous cycling.
UNASSIGNED: In a randomised crossover study design, eleven males (mean ± SD: age 25 ± 7 years) undertook bouts of moderate intensity continuous exercise [MICE, 30 min, 65%-70% maximum heart rate (HRmax)], high-volume high intensity interval exercise (HV-HIIE, 4 × 4 min, 80%-85% HRmax) and low-volume HIIE (LV-HIIE, 4 × 2 min, 90%-95% HRmax). The cumulative impact of each interval on circulating HSPC (CD34+CD45dimSSClow) and CD56dim concentrations (cells/µL), and the bone marrow homing potential of HSPCs (expression of CXCR-4 and VLA-4) were determined.
UNASSIGNED: There was an increase in HSPC concentration after two intervals of LV-HIIE (Rest: 1.84 ± 1.55 vs. Interval 2: 2.94 ± 1.34, P = 0.01) and three intervals of HV-HIIE only (Rest: 2.05 ± 0.86 vs. Interval 3: 2.51 ± 1.05, P = 0.04). The concentration of all leukocyte subsets increased after each trial, with this greatest for CD56dim NK cells, and in HIIE vs. MICE (LV-HIIE: 4.77 ± 2.82, HV-HIIE: 4.65 ± 2.06, MICE: 2.44 ± 0.77, P < 0.0001). These patterns were observed for concentration, not frequency of CXCR-4+ and VLA-4+ HSPCs, which was unaltered. There was a marginal decrease in VLA-4, but not CXCR-4 expression on exercise-mobilised HSPCs after all trials (P < 0.0001).
UNASSIGNED: The results of the present study indicate that HIIE caused a more marked increase in HSPC and CD56dim NK cell concentrations than MICE, with mobilised HSPCs maintaining their bone marrow homing phenotype. LV-HIIE evoked an increase in HSPC concentration after just 2 × 2-minute intervals. The feasibility and clinical utility of interval cycling in a PBSC donation context should therefore be evaluated.

BACKGROUND: Using natural killer (NK) cells to treat hematopoietic and solid tumors has great promise. Despite their availability from peripheral blood and cord blood, stem cell-derived NK cells provide an \"off-the-shelf\" solution.
METHODS: In this study, we developed two CAR-NK cells targeting PD-L1 derived from lentiviral transduction of human umbilical cord blood (UCB)-CD34+ cells and UCB-CD34+-derived NK cells. The transduction efficiencies and in vitro cytotoxic functions including degranulation, cytokine production, and cancer cell necrosis of both resultants PD-L1 CAR-NK cells were tested in vitro on two different PD-L1 low and high-expressing solid tumor cell lines.
RESULTS: Differentiated CAR‑modified UCB-CD34+ cells exhibited enhanced transduction efficiency. The expression of anti-PD-L1 CAR significantly (P < 0.05) enhanced the cytotoxicity of differentiated CAR‑modified UCB-CD34+ cells and CAR-modified UCB-CD34+-derived NK cells against PD-L1 high-expressing tumor cell line. In addition, CAR-modified UCB-CD34+-derived NK cells significantly (P < 0.05) restored the tumor-killing ability of exhausted PD-1 high T cells.
CONCLUSIONS: Considering the more efficient transduction in stem cells and the possibility of producing CAR-NK cell products with higher yields, this approach is recommended for studies in the field of CAR-NK cells. Also, a pre-clinical study is now necessary to evaluate the safety and efficacy of these two CAR-NK cells individually and in combination with other therapeutic approaches.

Allogeneic natural killer (NK) cell therapy has been effective in treating cancer. Many studies have tested NK cell therapy using human pluripotent stem cells (hPSCs). However, the impacts of the origin of PSC-NK cells on competence are unclear. In this study, several types of hPSCs, including human-induced PSCs (hiPSCs) generated from CD34+, CD3-CD56+, and CD56- cells in umbilical cord blood (UCB), three lines of human embryonic stem cells (hESCs, ES-1. ES-2 and ES-3) and MHC I knockout (B2M-KO)-ESCs were used to differentiate into NK cells and their capacities were analyzed. All PSC types could differentiate into NK cells. Among the iPSC-derived NK cells (iPSC-NKs) and ESC-derived NK cells (ES-NKs), 34+ iPSCs and ES-3 had a higher growth rate and cytotoxicity, respectively, ES-3 also showed better efficacy than 34+ iPSCs. B2M-KO was similar to the wild type. These results suggest that the screening for differentiation of PSCs into NK cells prior to selecting the PSC lines for the development of NK cell immunotherapy is an essential process for universal allotransplantation, including the chimeric antigen receptor (CAR).

Acute myeloid leukemia (AML) is a complex hematopoietic clonal disorder with limited curative options beyond stem cell transplantation. The success of transplant is intimately linked with the graft versus leukemia effect from the alloreactive donor immune cells including, T and NK cells. The immune system plays a dynamic role in leukemia survival and resistance. Despite our growing understanding of the immune microenvironment, responses to immune-based therapies differ greatly between patients. Herein, we review the biology of immune evasion mechanisms in AML, discuss the current landscape of immunotherapeutic strategies, and discuss the implications of therapeutic targets. This review focuses on T and NK cell-based therapy, including modified and non-modified NK cells, CAR-T and CAR-NK cells, antibodies, and checkpoint blockades. Understanding the complex interchange between immune tolerance and the emergence of tumor resistance will improve patient outcomes.

Natural killer (NK) cells are innate immune lymphocytes that rapidly produce cytokines upon activation and kill target cells. NK cells have been of particular interest in primary hemophagocytic lymphohistiocytosis (pHLH) since all of the genetic defects associated with this disorder cause diminished cytotoxic capacity of NK cells and T lymphocytes, and assays of NK cell killing are used clinically for the diagnosis of HLH. Herein, we review human NK cell biology and the significance of alterations in NK cell function in the diagnosis and pathogenesis of HLH.

OBJECTIVE: NK cells are essential for the detection, identification and prediction of cancer. However, so far, there is no prognostic risk model based on NK cell-related genes to predict the prognosis and treatment outcome of DLBCL patients. This study aimed to explore a risk assessment model that could accurately predict the prognosis and treatment efficacy of DLBCL.
METHODS: Bioinformatics analysis of the expression profiles of DLBCL samples in the GEO database was performed. Cox regression and LASSO regression analysis were used to determine NK cell-related genes associated with patient\'s prognosis. Based on these genes, a risk assessment model was constructed to predict the prognosis of patients and the effectiveness of treatment. Finally, qRT-PCR was used to verify the expression of gene tags in clinical samples.
RESULTS: We identified seven prognosis-related NK cell-related genes (MAP2K1, PRKCB, TNFRSF10B, IL18, LAMP1, RASGRP1, and SP110), and DLBCL patients were divided into low- and high-risk groups based on these genes. Survival analysis showed that the prognosis of patients with low-risk group was better. Pathway enrichment analysis showed that the differentially expressed genes between the two risk groups were related to immune response pathways. Compared with the high-risk group, the low-risk group had higher infiltration of immune cells in tumor tissues. Besides, compared with high-risk group, low-risk patients by immunotherapy or other commonly used anti-tumor drugs might have better efficacy after treatment. In addition, qRT-PCR showed that the expression of risk genes including TNFRSF10B, IL18 and LAMP1 were significantly increased in most DLBCL samples compared to control samples, while the expression of protective genes including MAP2K1, PRKCB, RASGRP1 and SP110 were significantly decreased.
CONCLUSIONS: The NK cell-related gene signatures were proved to be a reliable indicator of the success of immunotherapy in patients with DLBCL, thus providing a unique evaluation method.

Natural killer (NK) cell-based therapies have made great progress in treating both hematological and solid tumors. Their unique mechanism of action does not rely on antigen presentation to recognize and eliminate tumor cells, making them a promising approach for cancer immunotherapy. In this review, we present a comprehensive summary of the latest clinical data of the novel NK cell-based therapies from the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, highlighting the potential of these advancements to revolutionize the treatment of hematologic malignancies and solid tumors.

Liver fibrosis is characterized by chronic inflammatory responses and progressive fibrous scar formation. Macrophages play a central role in the pathogenesis of hepatic fibrosis by reconstructing the immune microenvironment. Picroside II (PIC II), extracted from Picrorhizae Rhizoma, has demonstrated therapeutic potential for various liver damage. However, the mechanisms by which macrophage polarization initiates immune cascades and contributes to the development of liver fibrosis, and whether this process can be influenced by PIC II, remain unclear. In the current study, RNA sequencing and multiple molecular approaches were utilized to explore the underlying mechanisms of PIC II against liver fibrosis in multidrug-resistance protein 2 knockout (Mdr2-/-) mice. Our findings indicate that PIC II activates M1-polarized macrophages to recruit natural killer cells (NK cells), potentially via the CXCL16-CXCR6 axis. Additionally, PIC II promotes the apoptosis of activated hepatic stellate cells (aHSCs) and enhances the cytotoxic effects of NK cells, while also reducing the formation of neutrophil extracellular traps (NETs). Notably, the anti-hepatic fibrosis effects associated with PIC II were largely reversed by macrophage depletion in Mdr2-/- mice. Collectively, our research suggests that PIC II is a potential candidate for halting the progression of liver fibrosis.