PD-1 Expression Research Articles

The effects of bone marrow humoral components of B-cell acute lymphoblastic leukemia patients on natural killer cell suppression.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common form of cancer diagnosed in children. While the majority of patients survive with conventional treatment, chemotherapeutic agents have adverse effects and the potential for relapse persists even after full recovery. Given their pivotal function in anti-cancer immunity, there has been a surge in research exploring the potential of natural killer (NK) cells in immunotherapy, which has emerged as a promising avenue for treating leukemia. Nevertheless, the efficacy of NK cell immunotherapy is less pronounced than expected, which suggests the external conditions that affect NK cell functions after the administration to patients with leukemia. In this study, the effects of humoral components in the bone marrow humoral components of B-ALL patients on healthy NK cells were investigated. Healthy peripheral blood mononuclear cells were cultured with and without bone marrow-derived plasma samples of B-ALL patients. The expression of PD-1 and IL-10 were found to be increased whereas the proliferative capacities of NK cells were found to be decreased at the presence of B-ALL plasma samples. Moreover, high IL-10 versus low IL-18 levels were detected in bone marrow plasma samples of B-ALL patients. These findings indicate that humoral components in the bone marrow of B-ALL patients exert a suppressive effect on NK cell functions.

Genetic predisposition to altered blood cell homeostasis is associated with glioma risk and survival

Glioma is a highly fatal and heterogeneous brain tumor with few known risk factors. Our study examines genetically predicted variability in blood cell indices in relation to glioma risk and survival in 3418 cases and 8156 controls. We find that increased platelet to lymphocyte ratio (PLR) confers an increased risk of glioma (odds ratio (OR) = 1.25, p = 0.005), especially tumors with isocitrate dehydrogenase (IDH) mutations (OR = 1.38, p = 0.007) and IDHmut 1p/19q intact (IDHmut-intact OR = 1.53, p = 0.004) tumors. Genetically inferred increased counts of lymphocytes (IDHmut-intact OR = 0.70, p = 0.004) and neutrophils (IDHmut OR = 0.69, p = 0.019; IDHmut-intact OR = 0.60, p = 0.009) show inverse associations with risk, which may reflect enhanced immune-surveillance. Considering survival, we observe higher mortality risk in patients with IDHmut 1p/19q with genetically predicted increased counts of lymphocytes (hazard ratio (HR) = 1.65, 95% CI: 1.24–2.20), neutrophils (HR = 1.49, 1.13–1.97), and eosinophils (HR = 1.59, 1.18–2.14). Polygenic scores for blood cell traits are also differentially associated with 17 tumor immune microenvironment features in a subtype-specific manner, including signatures related to interferon signaling, PD-1 expression, and T-cell/Cytotoxic responses. Our findings highlight immune-mediated susceptibility mechanisms with potential disease management implications.

Prognostic significance of programmed cell death 1 expression on CD8+T cells in various cancers: a systematic review and meta-analysis

BackgroundIncreased PD-1 expression on CD8+ T cells is considered as a hallmark for T-cell exhaustion, and is thought to be related to the prognosis of cancer patients. However, discrepant results have made it difficult to apply PD-1+CD8+T cells and tumor prognosis to clinical practice. Therefore, we conducted a meta-analysis to evaluate its prognostic value in human cancers.MethodsPRISMA reporting guidelines were strictly followed for conducting the current meta-analysis. The PubMed, Web of Science, Embase databases were searched from inception to November 2024. The pooled Hazard Ratio (HR) along with 95% confidence intervals (CIs) of each article were combined for the associations of PD-1+CD8+ T cells with overall survival (OS), progression- free survival (PFS) and disease-free survival(DFS). Subgroup analyses were performed for area, specimen type, cancer type, treatment, detected method and cancer stage.ResultsA total of 20 studies (23 cohorts, 3086 cancer patients) were included in our study. The expression PD-1+CD8+ T cells in cancer patients tended to predict poor overall survival (OS) (HR: 1.379, 95%CI: 1.084-1.753, p= 0.009), and unfavorable disease-free survival(DFS) (HR: 1.468, 95%CI: 0.931-2.316, p=0.099), though it did not reach statistical significance. Begg’s and Egger’s test demonstrated that no obvious publication bias was exist.ConclusionsHigh PD-1 expression on CD8+ T cells is associated with worse survival outcomes, which can be potentially used as a prognostic marker of malignant tumor.

Bryostatin-1 enhances the proliferation and functionality of exhausted CD8+ T cells by upregulating MAP Kinase 11

IntroductionBryostatin-1, a potent agonist of the protein kinase C, has been studied for HIV and cancer therapies. In HIV research, it has shown anti-HIV effects during acute infection and reactivation of latent HIV in chronic infection. As effective CD8+ T cell responses are essential for eliminating reactivated virus and achieving a cure, it is important to investigate how bryostatin-1 affects HIV-specific CD8+ T cells. HIV-specific CD8+ T cells often become exhausted, showing reduced proliferative potential and impaired cytokine production, a dysfunction also observed in cancer. Therefore, we further investigated how bryostatin-1 directly impacts exhausted CD8+ T cells.MethodsPBMCs from people with HIV (PWH) were treated with bryostatin-1 and tracked with proliferation dye for cell expansion. One day 6, HIV-specific CD8+ T cells were detected by tetramers staining and examined by flow cytometry. By utilizing an established in vitro murine T cell exhaustion system, changes in inhibitory receptors, transcription factors, cytokine production and killing capacity of bryostatin-1 treated exhausted CD8+ T cells were determined by flow cytometry. RNA-seq analysis was performed to study transcriptional changes in these cells.ResultsWe found that bryostatin-1 improved the expansion and decreased PD-1 expression of HIV-specific CD8+ T cells. Bryostatin-1 enhanced the functionality and proliferation while decreasing inhibitory receptor expression of in vitro generated exhausted CD8+ T cells. Bryostatin-1 upregulated TCF-1 and decreased TOX expression. These changes were confirmed through RNA-seq analysis. RNA-seq revealed that mitogen-activated protein kinases (MAPK) 11 was significantly downregulated in exhausted CD8+ T cells, however, it greatly upregulated after bryostatin-1 treatment. Inhibition of MAPK11 in bryostatin-1-treated cells blocked the increased proliferation and IFN-γ production induced by bryostatin-1, but did not affect other bryostatin-1 induced effects, such as the reduction of inhibitory receptors.DiscussionOur data demonstrate that bryostatin-1 induces a MAPK 11-dependent improvement in the proliferative and functional capacity of exhausted T cells. This study provides a rationale for bryostatin-1's potential to help eradicate the HIV reservoir during treatment, and it may also contribute to cancer immunotherapy by functionally improving exhausted CD8+ T cells.

Targeted intra-tumoral hyperthermia using uniquely biocompatible gold nanorods induces strong immunogenic cell death in two immunogenically ‘cold’ tumor models

IntroductionHyperthermia is an established adjunct in multimodal cancer treatments, with mechanisms including cell death, immune modulation, and vascular changes. Traditional hyperthermia applications are resource-intensive and often associated with patient morbidity, limiting their clinical accessibility. Gold nanorods (GNRs) offer a precise, minimally invasive alternative by leveraging near-infrared (NIR) light to deliver targeted hyperthermia therapy (THT). THT induces controlled tumor heating, promoting immunogenic cell death (ICD) and modulating the tumor microenvironment (TME) to enhance immune engagement. This study explores the synergistic potential of GNR-mediated THT with immunotherapies in immunogenically ‘cold’ tumors to achieve durable anti-tumor immunity.MethodsGNRs from Sona Nanotech Inc.™ were intratumorally injected and activated using NIR light to induce mild hyperthermia (42–48°C) for 5 minutes. Tumor responses were analyzed for cell death pathways and immune modulation. The immunogenic effects of THT were assessed alone and in combination with intratumoral interleukin-2 (i.t. IL-2) or systemic PD-1 immune checkpoint blockade. Immune cell infiltration, gene expression changes, and tumor growth kinetics were evaluated.ResultsTHT reduced tumor burden through cell death mechanisms, including upregulated ICD marked by calreticulin exposure within 48 hours. By 48 hours, CD45+ immune cell levels were increased, including increased levels of immunosuppressive M2 macrophages. While THT led to innate immune cell stimulations highlighted by gene expression upregulation in the STING cGAS pathway and enhanced M1 and dendritic cell levels, tumor regrowth was observed within six days post-treatment. To enhance THT's immunogenic effects, the therapy was combined with intratumoral interleukin-2 (i.t. IL-2) or systemic PD-1 immune checkpoint blockade. Sequential administration of i.t. IL-2 post-THT induced robust CD8+ T-cell infiltration and led to sustained tumor regression in both treated and distant tumors, accompanied by the emergence of memory T cells. However, IL-2-induced immunosuppressive T-reg populations were also sustained to tumor endpoint suggesting that therapy could be further enhanced. Additionally, PD-1 expression, which was upregulated in CD8+ T cells by THT, was targeted with systemic PD-1 inhibition, further augmenting immune engagement within the TME.DiscussionThese combinatory treatments demonstrated synergistic effects, promoting durable anti-tumor responses and immune memory. Collectively, GNR-mediated THT effectively reduces tumor burden and remodels the TME, potentiating systemic immunity and enhancing the impact of complementary immunotherapies.

The systematic analysis of genes related to butyrate metabolism suggests that CDKN3 could serve as a promising therapeutic target for lung adenocarcinoma treatment

BackgroundMetabolic pathways are known to significantly impact the development and advancement of lung cancer. This study sought to establish a signature related to butyrate metabolism that is specifically linked to lung adenocarcinoma (LUAD).MethodsFor the purpose of identifying butyrate metabolism-related differentially expressed genes (BMR-DEGs) in the TCGA-LUAD dataset, we introduced transcriptome data. This was followed by the implementation of the univariate Cox and LASSO analyses in order to construct a LUAD gene signature. We performed a comprehensive analysis of gene function enrichment between the two populations at risk, thoroughly examined their immune microenvironment characteristics, and assessed the effectiveness of immunotherapy. Finally, the function of CDKN3 in LUAD was verified by in vitro experiments.ResultsThrough a comprehensive analysis of the TCGA-LUAD dataset, 51 significant BMR-DEGs were confirmed. Subsequently, five characteristic genes, CPS1, ABCC2, CDKN3, SLC2A1, and IGFBP1 were identified to create prognostic features for butyrate metabolism related outcomes in LUAD. Cox regression analysis determined that the pathological T stage, tumor stage, and RiskScore could serve as independent prognostic indicators. Analysis of the abundance of 22 immune infiltrating cells revealed that 15 immune cell types exhibited substantial differences and were strongly associated with risk ratings and prognosis. An important correlation exists between risk ratings and immunological checkpoints, which can be utilized to forecast the efficacy of treatment. In the high-risk group, there was an upregulation of the expression of PD-L2, PD-L1, and PD-1. Additionally, the risk score showed a positive correlation with TIDE and Exclusion score, while showing a negative correlation with Dysfunction score. Furthermore, the IC50 values for cisplatin, paclitaxel, and docetaxel were notably elevated in the high-risk group, indicating that these medications could potentially provide therapeutic advantages for this particular group. Finally, we determined that knockdown CDKN3 inhibited the proliferation and metastasis of LUAD cells.ConclusionWe identify and validate a novel BMR-related prognostic signature comprising 5 DEGs for LUAD patients. Our data might provide a new molecular target for LUAD treatment.

Illuminating the impact of CD38-induced adenosine formation in B-cell lymphoma

The expression of CD38 by cancer cells may mediate an immune-suppressive effect by producing Extracellular Adenosine (ADO) acting through G-protein-coupled cell surface receptors on cellular components and tumor cells. This can increase PD-1 expression and interaction with PD-L1, suppressing CD8 + cytotoxic T cells. This study examines the impact of heightened CD38 expression and extracellular ADO on various hematological and clinical parameters in patients with mature B-cell lymphoma, alongside their correlation with the soluble counterparts of the PD-1/PD-L1 axis. Our study was conducted on 90 patients, CD38-positive and CD38-negative (measured by flow cytometry), with mature B-cell lymphoma divided into CLL and B-NHL subtypes. Their serum ADO, soluble PD-1, and PD-L1 levels were measured using a sandwich ELISA. Our study revealed a positive correlation between CD38 expression, sADO, sPD-1, and sPD-L1 in mature B-cell lymphoma patients. CD38-positive patients had higher sADO, sPD-1, and sPD-L1 levels. Higher CD38 expression and extracellular ADO negatively affected HB level and PLT count and positively correlated with the higher risk stratification in mature B-cell lymphoma patients. This study explored the potential impact of CD38 expression and elevated extracellular ADO on B-cell lymphoma alongside their link with the PD-1/PD-L1 axis. Our findings underscore the influence of extracellular ADO on the neoplastic process of mature B-cell lymphoma. We also propose targeting the CD38-induced-ADO formation pathway, which could serve as a promising therapeutic immune target with multifaceted effects within mature B-cell neoplasms.

Peripheral blood PD-1+T lymphocytes as biomarkers in liquid biopsies for solid tumors: Clinical significance and prognostic applications.

A shift toward a T cell exhaustion phenotype is associated with the upregulation of expression of programmed cell death protein 1 (PD-1) on T lymphocytes in patients with malignant solid tumors. The interaction between PD-1 and programmed death-ligand 1 (PD-L1) inhibits PD-1+ T lymphocyte function, impacting their anti-tumor immune activity. Immune checkpoint inhibitors targeting PD-1/PD-L1 have revolutionized the treatment of various solid malignancies, improving therapeutic efficacy and survival outcomes. Peripheral blood analysis of liquid biopsies is being increasingly used to identify populations most likely to benefit from various treatment modalities. PD-1+ T lymphocytes represent the primary cell population responsive to immunotherapeutic interventions for patients with solid malignancies, as evidenced by the altered PD-1 expression levels and proportion of cells comprising the overall population of immunocytes. PD-1+ T cells in peripheral blood exert an associative and reciprocal predictive effect on homologous intratumoral cells. Distinct subpopulations of PD-1+T cells exhibit differential ability to proliferate in the periphery and can be characterized by tumor antigen-specific and exhaustion phenotypes. These characteristics have prognostic implications, aiding in the prediction of the efficacy of antitumor therapy and predicting survival outcomes. We highlight distinct subpopulations of PD-1+T cells, their exhaustion and antigen-specific phenotypes, and their dynamic changes over treatment, providing insights into their utility for tailoring personalized therapies. For the first time, this review discusses the role of peripheral PD-1+T lymphocytes as prognostic biomarkers in liquid biopsies, focusing on their clinical significance, predictive value during therapy, and future research directions.

PD-L1, PD-1, and CTLA-4 mRNA InSitu Expression by Canine Oral Melanoma Cells and Immune Cells of the Tumour Microenvironment.

Canine oral melanoma (OM) exhibits poor prognosis and limited treatment options. The success of immune checkpoint inhibitors (ICIs) in human melanoma has driven interest in similar therapeutic approaches in the dog, although the immunosuppressive mechanisms adopted by canine OM remain unclear. This study aimed to evaluate the expression of the immune checkpoints PD-1/PD-L1 and CTLA-4 by RNAscope insitu hybridization (ISH) in canine OM, to investigate their expression pattern and explore their potential role in melanoma progression. Twenty-four formalin-fixed, paraffin-embedded canine OM were included in the study. PD-L1 expression by tumour cells was detected in 100% melanomas (score 1-3), especially at the host-tumour interface. PD-1 and CTLA-4 expression by tumour cells was detected in 13/24 (54%, score 1-2) and 18/24 (75%, score 1) melanomas, respectively. Dual ISH-immunohistochemistry with Melanoma Triple Cocktail, CD3, CD20 and Iba1 demonstrated the expression of tested immune checkpoints in neoplastic and immune cells. Notably, PD-1 and CTLA-4 were predominantly expressed by tumour-infiltrating T lymphocytes, while PD-L1 was primarily expressed by tumour-associated macrophages. PD-1 expression in neoplastic cells was significantly correlated with mitotic count (p < 0.05), while no associations were found between immune checkpoint expression and disease-free interval or overall survival. Whole tumour PD-L1 and PD-1 expression, assessed by image analysis, correlated to PD-L1 scores in neoplastic cells and the grade of tumour-infiltrating lymphocytes, respectively. Collectively, PD-L1, PD-1 and CTLA-4 likely contribute to immunosuppression in canine OM. Further studies are warranted to investigate whether ISH can serve as a biomarker for selecting patients suitable for ICI treatment.

CD55 characterizes regulatory T cells with reduced functionality and is downregulated in rheumatoid arthritis.

This study aimed to investigate the role of CD55 in regulatory T cells (Tregs) and clarify its clinical relevance in rheumatoid arthritis (RA). Flow cytometry was used to examine the expression of Helios and CTLA-4 in CD55+and CD55- Tregs in mouse peripheral blood and spleen. FoxP3EGFP mice were employed to analyze the in vitro inhibitory function of CD55+and CD55-Tregs. We compared CD55 expression and function in control and CIA mice. Additionally, the expression of Helios, PD-1, and TIGIT in CD55+Tregs was examined in healthy controls and RA patients. Correlation analysis and receiver operating characteristic (ROC) curves were used to assess the clinical utility of CD55-related T cell subgroups in RA diagnosis. High CD55 expression was observed in CD4+T cells and Tregs, with significantly higher levels in peripheral blood than in the spleen in mice. CD55-Tregs exhibited increased expression of Helios and CTLA-4, and a more pronounced suppressive function compared to CD55+Tregs in mice. Additionally, CD55 expression in Tregs from peripheral blood and spleen of CIA mice was significantly reduced. In humans, peripheral blood CD55- Tregs expressed higher levels of Helios and TIGIT. Moreover, CD55+Tregs were markedly reduced in RA patients and correlated with clinical indicators of RA, demonstrating potential as diagnostic markers. CD55+Tregs represent a subset of Tregs with weaker functionality and were decreased in RA and could assist the diagnosis of RA.

Parkin modulates the hepatocellular carcinoma microenvironment by regulating PD-1/PD-L1 signalling.

Parkin-mediated mitophagy is essential for clearing damaged mitochondria, and it inhibits tumour development. The role of mitophagy in modulating tumour immunity is becoming clearer, but the underlying mechanism is still poorly understood. This study was designed to examine the role of Parkin in the immune microenvironment of liver tumours induced by carbon tetrachloride (CCl4). Single-cell RNA sequencing analysis, Western blot, immunofluorescence and co-immunoprecipitation were used to verify the mechanism of Parkin affecting the tumour microenvironment by altering the expression of PD-1. Our data revealed that Park2-/- mice showed severe liver damage and increased malignancy. Single-cell RNA sequencing analysis of T lymphocytes in liver tumours showed that the number of cytotoxic CD8+ T cells (Gzmb/Ifng/Fasl) was significantly decreased and the number of exhausted CD8+ T cells (Pdcd1/Lag3/Tigit/Havcr2/Ctla4) was significantly increased in Park2-/- mice, indicating the immune suppressive microenvironment. Single-cell RNA sequencing analysis of myeloid-derived cells also displayed the increase of M2-like macrophages in Park2-/- mice. Through quantitative proteomic analysis, it was found that the differential protein expression between the two groups mainly localized in the plasma membrane and extracellular, including PD-1, MHC-Ⅰ molecules etc., and was mainly associated with PD-1 and antigen presentation pathways. It could impair the antitumour immune response with Parkin deficiency. Parkin deficiency leads to the decrease of hepatic mitophagy levels and the formation of an immune suppressive microenvironment, which promotes the tumourigenesis of liver cancer. As an E3 ubiquitin ligase, Parkin induces the ubiquitination and degradation of PD-1 in liver cancer and could influence antitumour immunity through the PD-1/PD-L1 signalling pathway. Thus, remodeling the tumour microenvironment through the reintroduction of Parkin or enhancement of mitophagy could activate the anti-tumour immune response and improve the immunotherapy efficacy, which may be a promising strategy for the treatment of HCC.

Preparation, characterization, and antitumor immunity activity of polysaccharide fractions from Radix Tinosporae in vivo

To investigate the preliminary structural characteristics and functions of polysaccharides from Radix Tinosporae, a neutral α-glucan polysaccharide, RTP-W with a molecular weight of 14.248 kDa was obtained. The potential therapeutic effect of RTP-W on hepatocellular carcinoma was investigated in vivo. Structural analysis revealed that RTP-W comprises a backbone of (1 → 4)-linked α-D-Glcp units with the occasional occupancy of α-Glcp-(1 → at the O-6 position for every nine α (1 → 4)-D-Glcp unit. Studies showed that RTP-W significantly protects the liver against cancer, extends the survival of mice with liver cancer, and lowers ALT, AST, and GGT levels in their blood. Further investigation revealed that RTP-W reversed the exhaustion of CD8+ T cells by reducing PD-1 expression and promoting cell proliferation and cytokine expression, primarily through the activation of the Akt signaling pathway. These findings indicate that RTP-W has promising potential as an immunomodulatory agent with antitumor effects.

5-Aza-2′-deoxycytidin (Decitabine) increases cancer-testis antigen expression in head and neck squamous cell carcinoma and modifies immune checkpoint expression, especially in CD39-positive CD8 and CD4 T cells

Failure of immunotherapy in head and neck squamous cell carcinoma (HNSCC) patients represents an unmet need to augment leverage of adaptive immunity. Immunogenic cancer-testis antigen (CTA) expression as well as lymphocyte differentiation and function are regulated by DNA methylation. Therefore, epigenetic therapy via inhibition of DNA-Methyltransferases by 5-Aza-2′-deoxycytidine (DAC) serves a promising adjuvant in immunotherapy.We investigated the effects of DAC on CTA expression and proliferative capacity in HNSCC cell lines and on the expression of 12 immune checkpoint molecules (ICM) on lymphocytes of oropharyngeal squamous cell carcinoma (OPSCC) patients and healthy donors.In all cell lines CTA were upregulated accompanied by decreased proliferation. In lymphocytes pronounced alterations of the ICM repertoire were observed, influenced by donor type and subpopulation. On CD39+ CD4 and CD8 T cells, the expression of co-stimulatory ICM GITR and OX40 increased dose dependently, whereas expression decreased on CD39- CD4 T cells. PD1 expression increased primarily on CD39+ CD8 T cells and decreased on CD39- CD4 T cells. CD27 expression decreased primarily in CD8 T cells, but increased in CD39- CD4 T cells, whereas ICOS expression was lowered in both CD39+ and CD39- subsets of CD4 as well as CD8 T cells.DAC treatment increased immunogenicity and decreased proliferation in HNSCC cells while enhancing expression of co-stimulatory ICM GITR and OX40. We propose low dose DAC treatment as a adjuvant to immunotherapy.

A non-randomised open-label exploratory 'window of opportunity' study of TG02 treatment in patients with locally advanced primary and recurrent RAS mutant colorectal cancer.

TG02 is a peptide-based cancer vaccine eliciting immune responses to oncogenic codon 12/13 RAS mutations. This phase 1 clinical trial (NCT02933944) assessed the safety and immunological efficacy of TG02 adjuvanted by GM-CSF in patients with KRAS-mutant colorectal cancer. In the interval between completing CRT and pelvic exenteration, patients with resectable KRAS mutation-positive, locally advanced primary or current colorectal cancer, received 5-6 doses of TG02/GM-CSF. Immune response was defined as a positive delayed-type hypersensitivity or positive T cell proliferation assay response. Tumour biopsies were analysed for tumour-infiltrating lymphocytes (TILs) and blood for CEA and ctDNA. TILs and tumouroids were cultured, characterised and tested for their killing efficacy. Six patients with rectal cancer were recruited to evaluate TG02. Three patients experienced a total of 16 treatment-related adverse events; all grade 1. Four of the 6 patients (66.7%) had at least one vaccine-induced TG02 immune response. Flow cytometry analysis showed high proportion of PD-1-expressing TILs in 2 of 3 patient specimens' post-treatment. A partial to near complete pathological response was reported in 4 of 6 patients. This study demonstrated that TG02/GM-CSF was well tolerated and induced a vaccine specific systemic immune response in the majority of patients. Low numbers limit conclusive clinical outcome reporting. High PD-1 expression on post-treatment TILs encourages the addition of an immune checkpoint inhibitor to TG02 and potentially other studies of peptide vaccines in future studies.

Tumor infiltration of inactive CD8 + T cells was associated with poor prognosis in Gastric Cancer.

Gastric cancer (GC) shows limited response to immune checkpoint inhibitors due to its complex tumor immune microenvironment (TIME). This study explores the functions of various immune cells in the complex TIME in GC. We assessed CD8 + T-cell infiltration of GC tissues by immunohistochemistry, and performed single-cell RNA sequencing (scRNA-seq) of tumor and normal tissues from 34 patients with GC. We categorized 157 GC patients into LOW, MID, and HIGH groups based on their CD8 + T-cell infiltration. Overall survival was notably lower for the HIGH and LOW groups compared with the MID group. Our scRNA-seq data analysis showed that CD8 + T-cell activity markers in the HIGH group were expressed at lower levels than in normal tissue, but the T-cell-attracting chemokine CCL5 was expressed at a higher level. Notably, CD8 + T-cells in the HIGH group displayed lower PD1 expression and higher CTLA4 expression. TCR repertoire analysis using only Epstein-Barr virus-negative cases showed that CD8 + T-cell receptor clonality was lower in the HIGH group than in the MID group. Furthermore, in the HIGH group, the antigen-presenting capacity of type 1 conventional dendritic cells was lower, the immunosuppressive capacity of myeloid-derived suppressor cells was higher, and the expression of CTLA4 in regulatory T-cells was higher. The present data suggest that the infiltration of inactive CD8 + T-cells with low clonality is induced by chemotaxis in the HIGH group, possibly leading to a poor prognosis for patients with GC.

HLA-E/Mtb specific CD4+ and CD8+ T cells have a memory phenotype in individuals with TB infection.

Tuberculosis (TB) is the deadliest infectious disease worldwide and novel vaccines are urgently needed. HLA-E is a virtually monomorphic antigen presentation molecule and is not downregulated upon HIV co-infection. HLA-E restricted Mtb specific CD8+ T cells are present in the circulation of individuals with active TB (aTB) and Mtb infection (TBI) with or without HIV co-infection, making HLA-E restricted T cells interesting vaccination targets for TB. Here, we performed in-depth phenotyping of HLA-E/Mtb specific and total T cell populations in individuals with TBI and in individuals with aTB or TBI and HIV using HLA-E/Mtb tetramers. We show that HIV co-infection is the main driver in changing the memory distribution of HLA-E/Mtb specific CD4+ and CD8+ T cell subsets. HLA-E/Mtb specific CD4+ and CD8+ T cells were found to circulate with comparable frequencies in all individuals and displayed expression of KLRG1, PD-1 and 2B4 similar to that of total T cells. The presence of HLA-E/Mtb specific T cells in individuals with aTB and TBI highlights the potential of HLA-E as a vaccine target for TB.

A case report of a patient with rheumatoid arthritis induced by checkpoint inhibitor treatment

Malignant melanoma occurs for only 1% of all skin neoplasms, but is characterized by the most aggressive clinical course and the lowest 5-year survival rate. Even after radical resection of patients in the non-metastatic stage, there is an increased risk of local recurrence and distant metastasis. Advances in molecular biology have aided the development of innovative targeted- and immunotherapies that have greatly improved patient prognosis. Among them is the suppression of the immune response through the expression of the transmembrane protein PD-L1 on the surface of neoplastic cells. Nivolumab is a humanized monoclonal antibody (so-called immune "check point" inhibitors), first-line treatment in patients with metastatic malignant melanoma and also used as an adjuvant treatment in patients at high risk of relapse, which is associated with PD-1 and therefore supports the inhibited T-cell immune response. This in turn leads to the risk of various autoimmune life-threatening adverse reactions. In clinical studies, immune-related adverse events of various degrees and severity have been described with the use of anti-PD-1 antibodies - immune-mediated colitis, pneumonitis, nephritis, hepatitis, dermatitis, arthritis, myositis, vasculitis, polymyalgia rheumatica, eosinophilic fasciitis and scleroderma. In rheumatology practice, the most frequently described cases of arthritis occur after a different period of time from the start of Nivolumab therapy. The specific mechanisms of the onset of immune-mediated arthritis in anti-PD-1 antibody therapy are not fully understood, but an overlapping pathogenesis with the onset of rheumatoid arthritis is suggested – PD-1 expression in the synovial fluid is a proven regulator of the T-cell immune response and is a possible future target for immunomodulatory therapy of rheumatoid arthritis (RA). We present a clinical case of a 52-year-old patient who developed RA following Nivolumab treatment. After temporarily discontinuation of Nivolumab, Methotrexate therapy was started and the patient showed a good clinical response after 3 months and reached minimal disease activity.

The impact of neoadjuvant immunotherapy on the clinical efficacy of stage IIIA-N2 non-small cell lung cancer patients.

To explore the impact of neoadjuvant immunotherapy on the clinical efficacy of stage IIIA-N2 non-small cell lung cancer (NSCLC) patients. The retrospective study was conducted on 120 patients with stage IIIA-N2 NSCLC admitted to our hospital during April 2020 to April 2022. The control group received local chemotherapy, while the combination group received neoadjuvant immunotherapy on the basis of chemotherapy. The treatment efficacy, immune function, PD-1 and PD-L1 (SP142) expression levels, and changes in inflammatory factors were compared between the two groups. Kaplan Meier survival curve was used to analyze the overall survival rate. Total effective rate in the control group was 53.33% (15.00% recovery+16.66% significant effect+21.66% effective), and the combined group had a higher total effective rate of 85.00% (41.66% recovery+23.33% significant effective+20.00% effective) (P<0.001). After intervention, the combination group had largely increased immune indicators levels, including CD3+, CD4+ and CD4+/CD8+ (P<0.001), but reduced levels of CD8+, PD-1 and PD-L1 (SP142) than the control group (P<0.001). After intervention, the levels of inflammatory factors in the combination group were also reduced than the control group (P<0.001). Compared to the control group with an adverse reaction rate of 31.66% (8.33% gastrointestinal reaction+11.66% hair loss+6.66% proteinuria+5.00% diarrhea), the combined group had much lower adverse reaction rate of 11.66% (1.66% gastrointestinal reaction+5.00% hair loss+3.33% proteinuria+1.66% diarrhea) (P<0.05). After 24months of follow-up, the overall survival rate was 58.33% (35/60) and 40.00% (24/60) in the combination group and the control group, respectively. The Kaplan Meier survival curve analysis showed a statistically significant difference in overall survival rate between the two groups (P<0.05). Neoadjuvant immunotherapy had a more significant therapeutic effect on stage IIIA-N2 NSCLC patients by reducing immunosuppressive and inflammatory factors, improving immune function, and reducing the occurrence of adverse reactions.

TIGIT+ CD4+ regulatory T cells enhance PD-1 expression on CD8+ T cells and promote tumor growth in a murine ovarian cancer model

Immune checkpoint-based immunotherapy has shown limited efficacy in the treatment of ovarian cancer. In recent years, the emergence of immune checkpoint co-targeting therapies, led by the combination targeting of TIGIT and FAK, has shown promise in ovarian cancer treatment. Our preliminary research indicates that TIGIT is predominantly expressed in regulatory T cells during ovarian cancer. However, the therapeutic impact of TIGIT targeting based on regulatory T cells in ovarian cancer remains to be elucidated. We utilized ID8 cells to establish a mouse model of ovarian cancer. Through flow cytometry and co-culture methods, we validated the relationship between the functionality of regulatory T cells and tumor masses, and confirmed the crucial role of TIGIT in immune suppression in ovarian cancer. Furthermore, using Foxp3-diphtheria toxin receptor (DTR) mice, we substantiated that the combined TIGIT antibody treatment, based on targeting regulatory T cells, effectively slowed down the progression of ovarian cancer. Taken together, our results have demonstrated that dual targeting of regulatory T cells and TIGIT effectively retards tumor growth, laying the groundwork for the clinical application of immune checkpoint combination therapies. Future research in ovarian cancer immunotherapy is leaning towards a strategy that combines multiple targets, and specific cell-type immunotherapies.

Prognostic and Immunologic Significance of SH2B2 in Colon Adenocarcinoma and its Relationship to Proliferation, Migration, and Invasion.

SH2B adaptor protein 2 (SH2B2, also named APS) is an adaptor protein implicated in the modulation of insulin signaling pathways and glucose metabolism. Its role in colon adenocarcinoma (COAD) is unknown. Data from The Cancer Genome Atlas and Gene Expression Omnibus database were utilized to assess SH2B2 expression and its clinical significance in COAD. We investigated the associations between SH2B2 expression with genomic instability, tumor mutational burden (TMB), DNA methylation, alternative splicing, immune infiltration, and drug sensitivity. A SH2B2 knockdown model was developed to examine its impact on COAD cellular functions. Highly expressed SH2B2 is associated with a poorer prognosis in COAD. SH2B2 expression in COAD is associated with copy number variations, microsatellite instability, methylation patterns, and alternative 5' splicing events, but not with TMB. SH2B2 is positively correlated with mostly immune cells and the expression of PD-1 and CTLA4. The IC50 values of ten drugs were significantly correlated with SH2B2 expression. BI-2536_1086 had a strong binding affinity with SH2B2. Furthermore, the knockdown of SH2B2 reduced the proliferation, migration, and invasion of COAD cells. SH2B2 appears to act as an oncogene in COAD and may serve as a pivotal prognostic and therapeutic target, deserving further exploration.