Natural killer cells: a future star for immunotherapy of head and neck squamous cell carcinoma.

The interplay between immune components and the epithelium plays a crucial role in the development and progression of head and neck squamous cell carcinoma (HNSCC). Natural killer (NK) cells, one of the main tumor-killing immune cell populations, have received increasing attention in HNSCC immunotherapy. In this review, we explore the mechanism underlying the interplay between NK cells and HNSCC. A series of immune evasion strategies utilized by cancer cells restrict HNSCC infiltration of NK cells. Overcoming these limitations can fully exploit the antineoplastic potential of NK cells. We also investigated the tumor-killing efficacy of NK cell-based immunotherapies, immunotherapeutic strategies, and new results from clinical trials. Notably, cetuximab, the most essential component of NK cell-based immunotherapy, inhibits the epidermal growth factor receptor (EGFR) signaling pathway and activates the immune system in conjunction with NK cells, inducing innate effector functions and improving patient prognosis. In addition, we compiled information on other areas for the improvement of patient prognosis using anti-EGFR receptor-based monoclonal antibody drugs and the underlying mechanisms and prognoses of new immunotherapeutic strategies for the treatment of HNSCC.

Secondary lymphomas of the skin.

Infection of the skin may be the result of an underlying disease, or lymphoma may be the primary cause. As a result, it is possible to differentiate between two types of lymphomas: primary cutaneous lymphoma and secondary cutaneous lymphoma (SCL), which is a type of systemic lymphoma that also affects the skin. The objective of the current review is to examine what is currently known about this neglected subject. Following this, SCL was examined from a clinical, histological, and survival perspective.

Paulownin elicits anti-tumor effects by enhancing NK cell cytotoxicity through JNK pathway activation.

Paulownin, a natural compound derived from Paulownia tomentosa wood, exhibits various physiological functions, including anti-bacterial and anti-fungal effects. However, the impact of paulownin on natural killer (NK) cell immune activity remains largely unknown. In this study, we investigated the effect of paulownin on NK cell activity both in vitro and in vivo, and explored its potential mechanisms. NK-92 cells were used for in vitro experiments and a BALB/c mouse model with B16F10 cells injected subcutaneously were used for in vivo anti-tumor analysis. We found that paulownin enhanced the cytolytic activity of NK-92 cells against leukemia, human colon, and human lung cancer cell lines. Paulownin treatment increased the expression of the degranulation marker protein CD107a and cytolytic granules, including granzyme B and perforin in NK-92 cells. Moreover, these enhancements of cytotoxicity and the expression of cytolytic granules induced by paulownin were also observed in human primary NK cells. Signaling studies showed that paulownin promoted the phosphorylation of JNK. The increased perforin expression and elevated cytotoxic activity induced by paulownin were effectively inhibited by pre-treatment with a JNK inhibitor. In vivo studies demonstrated that the administration of paulownin suppressed the growth of B16F10 melanoma cells allografted into mice. Paulownin administration promoted the activation of NK cells in the spleen of mice, resulting in enhanced cytotoxicity against YAC-1 cells. Moreover, the anti-tumor effects of paulownin were reduced upon the depletion of NK cells. Therefore, these results suggest that paulownin enhances NK cell cytotoxicity by activating the JNK signaling pathway and provide significant implications for developing new strategies for cancer immunotherapy.

Genetically defined causal effects of natural killer cells related traits in risk of infection: a Mendelian randomization study.

BACKGROUND: The intricate interplay between genetics and immunology often dictates the host's susceptibility to various diseases. This study explored the genetic causal relationship between natural killer (NK) cell-related traits and the risk of infection. METHODS: Single-nucleotide polymorphisms (SNPs) significantly associated with NK cell-related traits were selected as instrumental variables to estimate their genetic causal effects on infection. SNPs from a genome-wide association study (GWAS) on NK cell-related traits, including absolute cell counts, median fluorescence intensities reflecting surface antigen levels, and relative cell counts, were used as exposure instruments. Summary-level GWAS statistics of four phenotypes of infection were used as the outcome data. The exposure and outcome data were analyzed via the two-sample Mendelian randomization method. RESULTS: Each one standard deviation increase in the expression level of human leukocyte antigen (HLA)-DR on HLA-DR+ NK cells was associated with a lower risk of pneumonia (P < 0.05). An increased HLA-DR+ NK/CD3- lymphocyte ratio was related to a lower of risk of pneumonia (P  < 0.05). Each one standard deviation increase in the absolute count of HLA-DR+ NK cells was associated with a lower risk of both bacterial pneumonia and pneumonia (P < 0.05). An increased HLA-DR+ NK/NK ratio was associated with a decreased risk of both pneumonia and bacterial pneumonia (P < 0.05). The results were robust under all sensitivity analyses. No evidence for heterogeneity, pleiotropy, or potential reverse causality was detected. Notably, our analysis did not reveal any significant associations between NK cell-related traits and other phenotypes of infection, including cellulitis, cystitis, and intestinal infection. CONCLUSIONS: HLA-DR+ NK cells could be a novel immune cell trait associated with a lower risk of bacterial pneumonia or pneumonia.

Feeder cell training shapes the phenotype and function of in vitro expanded natural killer cells.

Natural killer (NK) cells are candidates for adoptive cell therapy, and the protocols for their activation and expansion profoundly influence their function and fate. The complexity of NK cell origin and feeder cell cues impacts the heterogeneity of expanded NK (eNK) cells. To explore this, we compared the phenotype and function of peripheral blood-derived NK (PB-NK) and umbilical cord blood-derived NK (UCB-NK) cells activated by common feeder cell lines, including K562, PLH, and 221.AEH. After first encounter, most PB-NK cells showed degranulation independently of cytokines production. Meanwhile, most UCB-NK cells did both. We observed that each feeder cell line uniquely influenced the activation, expansion, and ultimate fate of PB eNK and UCB eNK cells, determining whether they became cytokine producers or killer cells. In addition, they also affected the functional performance of NK cell subsets after expansion, that is, expanded conventional NK (ecNK) and expanded FcRγ- NK (eg-NK) cells. Hence, the regulation of eNK cell function largely depends on the NK cell source and the chosen expansion system. These results underscore the significance of selecting feeder cells for NK cell expansion from various sources, notably for customized adoptive cell therapies to yield cytokine-producing or cytotoxic eNK cells.

Single Cell Droplet-Based Efficacy and Transcriptomic Analysis of a Novel Anti-KLRG1 Antibody for Elimination of Autoreactive T Cells.

Progress in developing improvements in the treatment of autoimmune disease has been gradual, due to challenges presented by the nature of these conditions. Namely, the need to suppress a patient's immune response while maintaining the essential activity of the immune system in controlling disease. Targeted treatments to eliminate the autoreactive immune cells driving disease symptoms present a promising new option for major improvements in treatment efficacy and side effect management. Monoclonal antibody therapies can be applied to target autoreactive immune cells if the cells possess unique surface marker expression patterns. Killer cell lectin like receptor G1 (KLRG1) expression on autoreactive T cells presents an optimal target for this type of cell depleting antibody therapy. In this study, we apply a variety of in vitro screening methods to determine the efficacy of a novel anti-KLRG1 antibody at mediating specific natural killer (NK) cell mediated antibody-dependent cellular cytotoxicity (ADCC). The methods include single-cell droplet microfluidic techniques, allowing timelapse imaging and sorting based on cellular interactions. Included in this study is the development of a novel method of sorting cells using a droplet-sorting platform and a fluorescent calcium dye to separate cells based on CD16 recognition of cell-bound antibody. We applied this novel sorting method to visualize transcriptomic variation between NK cells that are or are not activated by binding the anti-KLRG1 antibody using RNA sequencing. The data in this study reveals a reliable and target-specific cytotoxicity of the cell depleting anti-KLRG1 antibody, and supports our droplet-sorting calcium assay as a novel method of sorting cells based on receptor activation.

NK cell receptors in anti-tumor and healthy tissue protection: Mechanisms and therapeutic advances.

Natural Killer (NK) cells are integral to the innate immune system, renowned for their ability to target and eliminate cancer cells without the need for antigen presentation, sparing normal tissues. These cells are crucial in cancer immunosurveillance due to their diverse array of activating and inhibitory receptors that modulate their cytotoxic activity. However, the tumor microenvironment can suppress NK cell function through various mechanisms. Over recent decades, research has focused on overcoming these tumor escape mechanisms. Initially, efforts concentrated on enhancing T cell activity, leading to impressive results with immunotherapeutic approaches aimed at boosting T cell responses. Nevertheless, a substantial number of patients do not benefit from these treatments and continue to seek effective alternatives. In this context, NK cells present a promising avenue for developing new treatments, given their potent cytotoxic capabilities, safety profile, and activity against T cell-resistant tumors, such as those lacking HLA-I expression. Recent advancements in immunotherapy include strategies to restore and amplify NK cell activity through immune checkpoint inhibitors, cytokines, adoptive NK cell therapy, and CAR-NK cell technology. This review provides a comprehensive overview of NK cell receptors, the tumor escape mechanisms that hinder NK cell function, and the evolving field of NK cell-based cancer immunotherapy, highlighting ongoing efforts to develop more effective and targeted cancer treatment strategies.

Innovative cell therapies for systemic sclerosis: available evidence and new perspectives.

INTRODUCTION: Systemic sclerosis (SSc) is the rheumatic disease with the highest individual mortality rate with a detrimental impact on quality of life. Cell-based therapies may offer new perspectives for this disease as recent phase I trials support the safety of IV infusion of allogeneic mesenchymal stromal cells in SSc and case reports highlight the potential use of Chimeric Antigen Receptor (CAR)-T cells targeting CD19 in active SSc patients who have not responded to conventional immunosuppressive therapies. AREAS COVERED: This narrative review highlights the most recent evidence supporting the use of cellular therapies in SSc as well as their potential mechanisms of action and discusses future perspectives for cell-based therapies in SSc. Medline/PubMed was used to identify the articles of interest, using the keywords 'Cellular therapies,' 'Mesenchymal stromal cells,' 'Chimeric Antigen Receptor' AND 'systemic sclerosis.' Milestones articles reported by the authors were also used. EXPERT OPINION: Cellular therapies may represent an opportunity for long-term remission/cure in patients with different autoimmune diseases, including SSc who have not responded to conventional therapies. Multiple ongoing phase I/II trials will provide greater insights into the efficacy and toxicity of cellular therapies.

Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer.

BACKGROUND: Major histocompatibility complex class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression. METHODS: We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFNγ-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single-cell neighborhoods from mIF images followed by multivariate discriminant analysis. RESULTS: Spatial quantitation of tumor cell MHC-I expression revealed intratumoral and intertumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56+ cell numbers in patient tumors were positively associated with disease-free survival (HR=0.58, p=0.064) and overall survival (OS) (HR=0.496, p=0.041). The OS association strengthened with high counts of both CD56+ and CD8+ cells (HR=0.199, p<1×10-3). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3+CD8+ T cells and CD3-CD56+ NK cells in MHC-I-bearing tumors (p<0.05). To infer associations of functional cell states and local cell-cell communication, we analyzed spatial single-cell neighborhood profiles to delineate the cellular environments of IFNγ+/- NK cells and T cells. We discovered that both IFNγ+ NK and CD8 T cells were more frequently associated with other IFNγ+ lymphocytes in comparison to IFNγ- NK cells and CD8 T cells (p<1×10-30). Moreover, IFNγ+ lymphocytes were most often found clustered near MHC-I+ tumor cells. CONCLUSIONS: Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Coassociation of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFNγ. Frequent colocalization of IFNγ+ NK cells with other IFNγ+ lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated.

NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer.

Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFß, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.

Maintaining the Balance: Regulation of NK Cell Activity.

Natural Killer (NK) cells, integral components of the innate immune system, play a crucial role in the protection against intracellular threats. Their cytotoxic power requires that activation is tightly controlled, and in this, they take a unique position within the immune system. Rather than depending on the engagement of a single activating receptor, their activation involves a delicate balance between inhibitory and activating signals mediated through an array of surface molecules. Only when this cumulative balance surpasses a specific threshold do NK cells initiate their activity. Remarkably, the activation threshold of NK cells remains robust even when cells express vastly different repertoires of inhibitory and activating receptors. These threshold values seem to be influenced by NK cell interactions with their environment during development and after release from the bone marrow. Understanding how NK cells integrate this intricate pattern of stimuli is an ongoing area of research, particularly relevant for cellular therapies seeking to harness the anti-cancer potential of these cells by modifying surface receptor expression. In this review, we will explore some of the current dogmas regarding NK cell activation and discuss recent literature addressing advances in our understanding of this field.

Large Extracellular Vesicles Derived from Natural Killer Cells Affect the Functions of Monocytes.

Communication between natural killer cells (NK cells) and monocytes/macrophages may play an important role in immunomodulation and regulation of inflammatory processes. The aim of this research was to investigate the impact of NK cell-derived large extracellular vesicles on monocyte function because this field is understudied. We studied how NK-cell derived large extracellular vesicles impact on THP-1 cells characteristics after coculturing: phenotype, functions were observed with flow cytometry. In this study, we demonstrated the ability of large extracellular vesicles produced by NK cells to integrate into the membranes of THP-1 cells and influence the viability, phenotype, and functional characteristics of the cells. The results obtained demonstrate the ability of large extracellular vesicles to act as an additional component in the immunomodulatory activity of NK cells in relation to monocytes.

Interleukin-37 exacerbates liver inflammation and promotes IFN-γ production in NK cells.

Interleukin (IL)-37, a unique member of the IL-1 family, is known for its anti-inflammatory properties. However, its effects on immune-mediated liver diseases, such as primary biliary cholangitis (PBC) and acute immune-mediated hepatitis, remain unclear. Using mouse models of autoimmune cholangitis and hepatitis induced by 2-OA-OVA and concanavalin A (Con A) respectively, we introduced the human IL-37 gene via a liver-preferred adeno-associated virus vector (AAV-IL-37) to mice, as mice lack endogenous IL-37. Our findings reveal that IL-37 did not affect autoimmune cholangitis. Surprisingly, IL-37 exacerbated inflammation in Con A-induced hepatitis rather than mitigating it. Mechanistic insights suggest that this exacerbation involves the interferon (IFN)-γ pathway, supported by elevated serum IFN-γ levels in AAV-IL-37-treated Con A mice. Specifically, IL-37 heightened the number of hepatic NK and NKT cells, increased the production of the NK cell chemoattractant CCL5, and elevated the frequency of hepatic NK and NKT cells expressing IFN-γ. Moreover, IL-37 enhanced IFN-γ secretion from NK cells when combined with other proinflammatory cytokines, highlighting its synergistic effect in promoting IFN-γ production. These unexpected outcomes underscore a novel role for IL-37 in exacerbating liver inflammation during immune-mediated liver diseases, implicating its influence on NK cells and the production of IFN-γ by these cells.

Non-viral approaches in CAR-NK cell engineering: connecting natural killer cell biology and gene delivery.

Natural Killer (NK) cells are exciting candidates for cancer immunotherapy with potent innate cytotoxicity and distinct advantages over T cells for Chimeric Antigen Receptor (CAR) therapy. Concerns regarding the safety, cost, and scalability of viral vectors has ignited research into non-viral alternatives for gene delivery. This review comprehensively analyses recent advancements and challenges with non-viral genetic modification of NK cells for allogeneic CAR-NK therapies. Non-viral alternatives including electroporation and multifunctional nanoparticles are interrogated with respect to CAR expression and translational responses. Crucially, the link between NK cell biology and design of drug delivery technologies are made, which is essential for development of future non-viral approaches. This review provides valuable insights into the current state of non-viral CAR-NK cell engineering, aimed at realising the full potential of NK cell-based immunotherapies.

Clinical and Paraclinical Features, Outcome, and Prognosis of Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: A Retrospective Study of 31 Vietnamese Patients.

Background: Extranodal natural killer (NK)/T-cell lymphoma, nasal type is a rare, aggressive, and poor prognostic subtype. The concurrent chemoradiotherapy followed by chemotherapy showed a relatively high response rate and the toxicity due to the treatment is acceptable. The study attempted to report the clinicopathological features, the survival outcome, and response rates of stages I-II, nasal type ENKTL patients treated with CCRT followed by adjuvant VIPD chemotherapy in Vietnam. Materials and Methods: The current study was conducted on 31 stage I or II NK/T cell lymphoma, nasal-type patients received by CCRT, followed by adjuvant VIPD chemotherapy. Information on patient demographics, disease stage, clinical symptoms, tumor, and paraclinical characteristics were collected. The primary endpoints of this study were OS and response rates. Results: After CCRT, 26 out of 31 (83.9%) patients had stable disease or response. Overall response rate (ORR) was observed in 80.6% of patients with a complete response rate of 67.7%. Low-risk PINK patients had a higher response rate than the intermediate- risk group (p=0.038). Mean disease-free survival was 44.3±4.5 months (95% CI, 35.4-53.1 months). Mean overall survival was 46.8±4.5 months (95% CI, 37.99-55.8 months). The intermediate-risk PINK patients had a significantly lower OS rate than low-risk patients. Conclusion: Concurrent chemoradiotherapy followed by adjuvant VIPD chemotherapy showed a high response rate and survival benefit in stages I-II, nasal type, and extranodal natural killer (NK)/T-cell lymphoma Vietnamese patients.

Aprepitant's roles in abating seizures, behavioral, and cognitive deficits in mice model of epilepsy.

BACKGROUND: Aprepitant (APR), a neurokinin 1 receptor antagonist, is an approved drug for treating chemotherapy-induced nausea and vomiting. OBJECTIVES: Investigate the beneficial roles of APR alone or in combination with sodium valproate (VPA) against lithium pilocarpine [li-pilo]-induced seizures, behavioral changes, and cognitive deficits. METHODS: Thirty male mice were divided into five groups, each containing 6. "Vehicle Group I," "Control Group II "li-pilo, " Valproate (VPA) group III (400 mg/kg/i.p.), "APR group IV, " and "Combination Group V." Videos of mice were recorded, and they were watched for episodes of spontaneous recurring seizures (SRS). Behavioral Tests were performed. At the end of the study, animal brains were taken for biochemical assays and gene expression studies. RESULTS: APR partially protected against SRS with partial restoration of average behavioral and standard cognitive skills associated with a significant increase in brain SOD activity and a significant decrease in MDA, IL-1ß, NF-КB, and SP-3 levels in relation to the control group. Interestingly, a combination of APR with VPA in epileptic mice showed complete protection against li-pilo-induced behavioral changes and cognitive deficits, a significant increase in brain SOD activity, and a considerable decrease in MDA, IL-1ß, NF-ΚB, and SP levels to normal. CONCLUSION: Using APR as an adjuvant to VPA is more effective in protecting against li-pilo-induced seizures, behavioral changes, and cognitive deficits due to its antioxidant, anti-inflammatory, and NK1 antagonist effects than using APR alone as drug therapy.

Vaccine induced mucosal and systemic memory NK/ILCs elicit decreased risk of SIV/SHIV acquisition.

SIV and HIV-based envelope V1-deleted (ΔV1) vaccines, delivered systemically by the DNA/ALVAC/gp120 platform, decrease the risk of mucosal SIV or SHIV acquisition more effectively than V1-replete vaccines. Here we investigated the induction of mucosal and systemic memory-like NK cells as well as antigen-reactive ILC response by DNA/ALVAC/gp120-based vaccination and their role against SIV/SHIV infection. ΔV1 HIV vaccination elicited a higher level of mucosal TNF-α+ and CD107+ memory-like NK cells than V1-replete vaccination, suggesting immunogen dependence. Mucosal memory-like NK cells, systemic granzyme B+ memory NK cells, and vaccine-induced mucosal envelope antigen-reactive IL-17+ NKp44+ ILCs, IL-17+ ILC3s, and IL-13+ ILC2 subsets were linked to a lower risk of virus acquisition. Additionally, mucosal memory-like NK cells and mucosal env-reactive IFN-γ+ ILC1s and env- reactive IL-13+ ILC2 subsets correlated with viral load control. We further observed a positive correlation between post-vaccination systemic and mucosal memory-like NK cells, suggesting vaccination enhances the presence of these cells in both compartments. Mucosal and systemic memory-like NK cells positively correlated with V2-specific ADCC responses, a reproducible correlate of reduced risk of SIV/HIV infection. In contrast, an increased risk was associated with the level of mucosal PMA/Ionomycin-induced IFN-γ+ and CD107+ NKG2A-NKp44- ILCs. Plasma proteomic analyses demonstrated that suppression of mucosal memory-like NK cells was linked to the level of CCL-19, LT-α, TNFSF-12, and IL-15, suppression of systemic env-reactive granzyme B+ memory-like NK cells was associated with the level of OLR1, CCL-3, and OSM, and suppression of IL-17+ ILCs immunity was correlated with the level of IL-6 and CXCL-9. In contrast, FLT3 ligand was associated with promotion of protective mucosal env-reactive IL-17+ responses. These findings emphasize the importance of mucosal memory-like NK cell and envelope- reactive ILC responses for protection against mucosal SIV/SHIV acquisition.

Enhancing Therapeutic Efficacy of FLT3 Inhibitors with Combination Therapy for Treatment of Acute Myeloid Leukemia.

FMS-like tyrosine kinase 3 (FLT3) mutations are genetic changes found in approximately thirty percent of patients with acute myeloid leukemia (AML). FLT3 mutations in AML represent a challenging clinical scenario characterized by a high rate of relapse, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The advent of FLT3 tyrosine kinase inhibitors (TKIs), such as midostaurin and gilteritinib, has shown promise in achieving complete remission. However, a substantial proportion of patients still experience relapse following TKI treatment, necessitating innovative therapeutic strategies. This review critically addresses the current landscape of TKI treatments for FLT3+ AML, with a particular focus on gilteritinib. Gilteritinib, a highly selective FLT3 inhibitor, has demonstrated efficacy in targeting the mutant FLT3 receptor, thereby inhibiting aberrant signaling pathways that drive leukemic proliferation. However, monotherapy with TKIs may not be sufficient to eradicate AML blasts. Specifically, we provide evidence for integrating gilteritinib with mammalian targets of rapamycin (mTOR) inhibitors and interleukin-15 (IL-15) complexes. The combination of gilteritinib, mTOR inhibitors, and IL-15 complexes presents a compelling strategy to enhance the eradication of AML blasts and enhance NK cell killing, offering a potential for improved patient outcomes.

HLA-E and NKG2A Mediate Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is the primary treatment for non-muscle-invasive bladder cancer (NMIBC), known to stimulate inflammatory cytokines, notably interferon (IFN)-γ. We observed that prolonged IFN-γ exposure fosters adaptive resistance in recurrent tumors, aiding immune evasion and tumor proliferation. We identify HLA-E and NKG2A, part of a novel NK and T cell checkpoint pathway, as key mediators of resistance in BCG-unresponsive NMIBC. IFN-γ enhances HLA-E and PD-L1 expression in recurrent tumors, with an enrichment of intra-tumoral NKG2A-expressing NK and CD8 T cells. CXCL9+ macrophages and dendritic cells and CXCL12-expressing stromal cells likely recruit CXCR3/CXCR4-expressing NK and T cells and CXCR7+ HLA-EHIGH tumor cells. NK and CD8 T cells remain functional within BCG-unresponsive tumors but are inhibited by HLA-E and PD-L1, providing a framework for combined NKG2A and PD-L1 blockade strategy for bladder-sparing treatment of BCG-unresponsive NMIBC.

[Immunological and neuroanatomic markers of the clinical dynamics of MCI and pre-MCI]. / Immunologicheskie i neiroanatomicheskie markery dinamiki dodementnykh kognitivnykh rasstroistv pri neiroreabilitatsii.

OBJECTIVE: To study the relationship of the parameters of immunity and systemic inflammation with the structural magnetic resonance imaging (MRI) parameters in patients with mild cognitive impairment (MCI) and pre-MCI undergoing neurocognitive rehabilitation to search for candidate markers of its effectiveness. MATERIAL AND METHODS: The main group included 49 patients, aged ≥60 years, with MCI and pre-MCI with memory impairment, who underwent a course of neurorehabilitation for 5 weeks. The control group included 19 volunteers of similar age with a total MoCA score of ≥25, who did not have cognitive impairment and immuno-inflammatory disorders. The parameters of cellular and humoral immunity and markers of inflammation were studied, and structural MRI was performed. RESULTS: The content of activated natural killer cells (NK-cells) was increased in MCI and pre-MCI (0.63±0.12% vs. 0.22±0.07% in the control group, p=2.2·10-7). The level of immunoglobulin G (IgG) <12.5 g/l in patients with MCI and pre-MCI with the Montreal Cognitive Assessment Scale (MoCA) score <22 was associated with a decrease in the volume of the right nucleus accumbens (376±35 mm3 in patients with IgG <12.5 g/l (p=0.0013) and 480±44 mm3 at IgG <12.5 g/l, 480±44 mm3 in the control group), as well as with a decrease of the thickness and volume of a number of other cortical zones. A logistic regression model including the level of immunoglobulin G, NK cells, CD8+ NK cells and right amygdala volume was constructed to predict the number of MoCA scores 6 months after the course of rehabilitation (R2=0.57; p<1·10-5; standard error of estimate: 2.93). CONCLUSION: As a result of this work, the perspectives of assessing the immunological parameters in combination with socio-demographic data and morphometric changes of the brain as potential prognostic markers of the dynamics of cognitive impairment in patients with MCI and pre-MCI after neurorehabilitation has been shown.