Levels Of CD4 Research Articles

Prognostic relevance of sarcopenia and tumor‐infiltrating CD8+ T cells in patients with hepatocellular carcinoma

AbstractAimThe relationship between sarcopenia, tumor‐infiltrating lymphocytes (TILs), and long‐term survival in patients with hepatocellular carcinoma (HCC) has not been investigated. We aimed to evaluate the prognostic relevance of sarcopenia and TILs in patients with HCC.MethodsWe included 351 patients with HCC following liver resection. Sarcopenia was defined based on the skeletal muscle index using computed tomography. Tumor‐infiltrating CD4+ and CD8+ T cells, perforin, and granzyme B were examined in liver resection specimens.ResultsSarcopenia patients had a significantly lower lymphocyte count (p = 0.003), prognostic nutritional index (p = 0.017), and CD4+ and CD8+ T cell counts (p = 0.008 and p = 0.006, respectively). The overall survival (OS) and recurrence‐free survival (RFS) rates of sarcopenia patients were significantly lower than non‐sarcopenia patients (both p < 0.001). Multivariate analysis revealed that sarcopenia and low CD8 levels were strong independent poor prognostic factors for OS and RFS (both p < 0.001). Regardless of sarcopenia, patients with high CD8 levels had significantly better OS and RFS rates and increased expression of perforin and granzyme B. Particularly, sarcopenia patients with high CD8 levels had much better OS and RFS than those with low CD8 levels and were even comparable to non‐sarcopenia patients with high CD8 levels.ConclusionsSarcopenia and low CD8 levels are strong independent poor prognostic factors in patients with HCC. Furthermore, sarcopenia patients with high CD8 levels had favorable survival and activated local immunity, suggesting that tumor‐infiltrating CD8+ T cells may play a functionally important role in sarcopenia patients.

Exposure to HIV is associated with altered composition of maternal microchimeric T cells in infants.

HIV exposed but uninfected infants (iHEU) display altered immunity and are at increased risk of infection. We previously reported that iHEU have decreased maternal microchimerism (MMc)-maternal cells transferred to the offspring in utero/during breastfeeding. We quantified MMc in T cell subpopulations in iHEU and unexposed infants (iHU) to determine whether a selective deficiency in MMc contributes to altered cellular immunity. Across all infants, MMc levels were highest in CD8+ T cells; however, the level of CD8+ T cell MMc was lower in iHEU versus iHU. In limited functional studies, we did not identify CMV-specific MMc during infant primary infection.

Effect of multidisciplinary team-style continuity of care and nutritional nursing on lung cancer: randomized study.

Aim: The clinical efficacy of systemic chemotherapy is limited due to the nonspecific delivery of anticancer drugs and is associated with serious systemic adverse effects. Therefore, integrated treatment and comprehensive care are particularly important for postoperative chemotherapy patients with lung cancer.Materials & methods: This study aimed to ascertain the application effect of multidisciplinary team (MDT)-style continuity of care combined with whole-process nutritional nursing in postoperative chemotherapy patients with lung cancer. Nutritional indices, immune function, adverse emotions, self-efficacy, self-care ability, quality of life and toxic reactions during chemotherapy were recorded in postoperative chemotherapy patients with lung cancer receiving routine care (control group) and MDT-style continuity of care combined with whole-process nutritional care (intervention group).Results: After care, the intervention group performed higher BMI, PA, TP and ALB, CD3+, CD4+ and CD4+/CD8+, lower levels of CD8+, lower self-rating anxiety scale, self-rating depression scale and QLQ-C30 symptom domain scores and higher general self-efficacy scale, exercise of self-care agency scale and QLQ-C30 functional domain scores versus the control group (all p<0.05).Conclusion: MDT-style continuity of care combined with whole-process nutritional care can improve the nutritional status of postoperative chemotherapy patients with lung cancer, and in turn enhance their quality of life.

Comparative Analysis of Extracellular Vesicles from Cytotoxic CD8+ αβ T Cells and γδ T Cells.

Although belonging to different branches of the immune system, cytotoxic CD8+ αβ T cells and γδ T cells utilize common cytolytic effectors including FasL, granzymes, perforin and granulysin. The effector proteins are stored in different subsets of lysosome-related effector vesicles (LREVs) and released to the immunological synapse upon target cell encounter. Notably, in activated cells, LREVs and potentially other vesicles are continuously produced and released as extracellular vesicles (EVs). Presumably, EVs serve as mediators of intercellular communication in the local microenvironment or at distant sites. EVs of activated and expanded cytotoxic CD8+ αβ T cells or γδ T cells were enriched from culture supernatants by differential and ultracentrifugation and characterized by nanoparticle tracking analyses and Western blotting. For a comparative proteomic profiling, EV preparations from both cell types were isobaric labeled with tandem mass tags (TMT10plex) and subjected to mass spectrometry analysis. 686 proteins were quantified in EV preparations of cytotoxic CD8+ αβ T cells and γδ T cells. Both populations shared a major set of similarly abundant proteins, while much fewer proteins presented higher abundance levels in either CD8+ αβ T cells or γδ T cells. To our knowledge, we provide the first comparative analysis of EVs from cytotoxic CD8+ αβ T cells and γδ T cells.

Intranasal Prime-Boost with Spike Vectors Generates Antibody and T-Cell Responses at the Site of SARS-CoV-2 Infection.

Long-lived, re-activatable immunity to SARS-CoV-2 and its emerging variants will rely on T cells recognizing conserved regions of viral proteins across strains. Heterologous prime-boost regimens can elicit elevated levels of circulating CD8+ T cells that provide a reservoir of first responders upon viral infection. Although most vaccines are currently delivered intramuscularly (IM), the initial site of infection is the nasal cavity. Here, we tested the hypothesis that a heterologous prime and boost vaccine regimen delivered intranasally (IN) will generate improved immune responses locally at the site of virus infection compared to intramuscular vaccine/booster regimens. In a transgenic human ACE2 murine model, both a Spike-expressing single-cycle adenovirus (SC-Ad) and an IFNß safety-enhanced replication-competent Vesicular Stomatitis Virus (VSV) platform generated anti-Spike antibody and T-cell responses that diminished with age. Although SC-Ad-Spike boosted a prime with VSV-Spike-mIFNß, SC-Ad-Spike alone induced maximal levels of IgG, IgA, and CD8+ T-cell responses. There were significant differences in T-cell responses in spleens compared to lungs, and the intranasal boost was significantly superior to the intramuscular boost in generating sentinel immune effectors at the site of the virus encounter in the lungs. These data show that serious consideration should be given to intranasal boosting with anti-SARS-CoV-2 vaccines.

Association between tumour-infiltrating lymphocyte-T CD8+ and programmed death-ligand 1 protein with the occurrence of metastasis in colorectal cancer patients: An observational study

Background: Tumour-infiltrating lymphocytes CD8+ (TILs CD8+) as an anticancer immune response and Programmed Death-Ligand 1 (PD-L1) as an immune checkpoint molecule expression are important in colorectal cancer (CRC) as their expression correlates with the immune status and the progression of cancer. The primary objective of this study is to examine the relationship between TILs CD8+ and PD-L1 expression levels and CRC metastasis to provide insights into the immune microenvironment’s role in CRC progression and metastasis, potentially improving patient outcomes and treatment response. Methods: This study was an observational study involving colorectal cancer patients who were treated at a tertiary hospital in Bandung, West Java, Indonesia. There were 40 patients included in the study. Tumour tissue samples were collected from patients, and immunohistochemical staining was performed to evaluate TILs CD8+ infiltration and PD-L1 expression levels. Clinical data, including metastasis occurrences, were collected from the cancer registry. Results: Analysis of TILs CD8+ and PD-L1 expression levels in CRC patients revealed significant findings regarding metastasis occurrence and cancer staging. There was a notable positive correlation between PD-L1 expression and TILs-CD8+ infiltration in the presence of distant metastasis and advanced cancer stage (p &lt; 0.05). However, no significant association was observed between TILs CD8 and PD-L1 expression levels and lymphatic metastasis. Conclusion: This study highlights the potential prognostic value of TILs CD8+ and PD-L1 expression levels in predicting CRC progression and metastasis. However, the lack of a significant correlation with lymphatic metastasis suggests the need for further investigation into the underlying mechanisms. Understanding the roles of PD-L1 and TILs-CD8+ expression in CRC metastasis may facilitate the development of targeted therapeutic strategies to improve patient outcomes.

B cell deficiency in thymoma tissues of Good’s syndrome patients

ObjectivesGood’s syndrome (GS) is a rare secondary immunodeficiency which is characterized by hypogammaglobulinemia and thymoma. This study aims to investigate the expression and distribution of B cells in thymoma tissue, given that B cells had been found to be reduced or absent in peripheral blood or bone marrow.MethodsThis study retrospectively analyzed thymoma tissues from 5 GS patients at the First Affiliated Hospital of Wenzhou Medical University and Zhejiang Provincial People’s Hospital. Tissues from 20 patients with simple thymoma were used as controls. Immunohistochemistry analyses were performed to detect the markers CD19, CD20, PAX5 and CD138 to evaluate the expression of B cells or plasma cells.ResultsCompared to the control group, 4 GS patients exhibited a complete absence of B cells in their thymoma tissue, while 1 GS patient exhibited a notable reduction in B cells. The expression levels of CD19, CD20 and PAX5 in the thymoma tissues of GS patients were dramatically lower than those in the control group (0 vs. 85%, 20 vs. 85%, 20 vs. 85%, respectively; P < 0.05). However, no significant difference was observed in the expression frequency of CD138 between the thymoma tissues of the two groups (0 vs. 30%, P > 0.05).ConclusionThis is the first report of B cell deficiency in 5 thymoma tissues of GS patients.

Tissue and imaging biomarkers of response to neoadjuvant nivolumab or nivolumab plus ipilimumab in patients with resectable hepatocellular carcinoma.

Perioperative immunotherapy has shown promise in some patients with early-stage hepatocellular carcinoma (HCC). This study examined tissue and imaging biomarkers associated with pathologic response in a phase II clinical trial in patients with resectable HCC. Analysis included 18 patients with biopsy-proven resectable HCC treated with neoadjuvant nivolumab plus ipilimumab or nivolumab alone in a phase II clinical trial at MD Anderson Cancer Center (NCT03222076). Liver MRE (to measure tissue fibrosis) and biopsies (to evaluate immune activation markers) were obtained serially pretreatment and after completing neoadjuvant immunotherapy. A major pathologic response (MPR) was defined as tumor necrosis of more than 70%. Data comparing patients with MPR versus those without was summarized using descriptive statistics and compared using the Wilcoxon rank sum test. Patients with MPR after neoadjuvant immunotherapy tended to have larger tumors (mean 9.52 vs. 4.99 centimeters; p = 0.050). They had a significant reduction in tumor size post-treatment (14.67% reduction vs. 9.15% increase in size; p = 0.042) and a non-significant decrease in serum AFP (-24.20% vs -14.00%; p = 0.085). Further, patients with MPR had a greater increase in intratumoral expression levels of CD8 (26.92% vs -0.04%; p = 0.026), Granzyme B (15.56% vs -2.24%; p = 0.011), and PD-1 (20.17% vs 0.40%; p = 0.048) but not PD-L1 (7.69% vs 0.57%; p = 0.26). Tumor and liver fibrosis were comparable before and after neoadjuvant therapy in patients with MPR versus non-responders. Changes in tumor size and immune cell infiltration and activation are candidate predictive markers of pathologic response to neoadjuvant immunotherapy in patients with resectable HCC.

Analysis of the expression characteristics and clinical value of immune function indicators in patients with human immunodeficiency virus infection

Objective: To explore the expression characteristics and clinical value of immune function indicators in patients with human immunodeficiency virus (HIV) infection. Methods: In this retrospective study, clinical data of 196 patients with HIV infection (observation group) and 196 health examinees (control group) admitted to our hospital from November 2021 to March 2023 were retrospectively analyzed. Patients in the observation group were further classified based on the staging as acute phase (n=53), asymptomatic phase (n=65), and acquired immunodeficiency (AIDS) phase (n=78). Levels of immune function indicators in the observation group and the control group were compared, and the correlation between immune function index levels and disease staging was analyzed. Results: Levels of CD3+, CD4+, CD4+/CD8+, B cells, and NK cells were lower in the observation group (P&lt;0.05), were significantly lower in asymptomatic patients compared with patients in the acute phase (P&lt;0.05), and were significantly lower in patients with AIDS than those in asymptomatic patients (P&lt;0.05). The results for CD8+ were in contrast to the above(P&lt;0.05). Spearman analysis confirmed that levels of CD3+, CD4+, CD4+/CD8+, B cells and NK cells significantly negatively correlated, and levels of CD8+ significantly positively correlated with the stages of HIV (P&lt;0.05). Conclusions: The immune function indicators of patients with HIV infection are markedly abnormal, which is mainly manifested by the decreased levels of CD3+, CD4+, CD4+/CD8+, B cells and NK cells, and the increased levels of CD8+. The profile of the immune function indicators correlates with the progressive severity of the disease. doi: https://doi.org/10.12669/pjms.40.10.9895 How to cite this: Wang N, Zeng T. Analysis of the expression characteristics and clinical value of immune function indicators in patients with human immunodeficiency virus infection. Pak J Med Sci. 2024;40(10):2233-2237. doi: https://doi.org/10.12669/pjms.40.10.9895 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

A Pan-Cancer Analysis of GAPDH as a Common Biomarker for Various Cancers

Background: The present study aimed to investigate the expression level of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and explore its prognostic value across 24 different human cancers. This investigation was conducted using comprehensive bioinformatics and in vitro approaches that involved multiple layers of analysis. Methods: GAPDH expression and methylation levels were assessed via bioinformatics tools and validated using cell lines through RNA sequencing and targeted bisulfite sequencing analyses. The potential prognostic significance of GAPDH was evaluated through the use of a Kaplan–Meier plotter. Additionally, cBioPortal was employed to investigate genetic alterations associated with this gene. Pathway analysis was conducted using DAVID. Furthermore, a correlation analysis between GAPDH expression and CD8+ T immune cells was performed using TIMER and CDT. Lastly, a gene-drug interaction network analysis was conducted using Cytoscape to examine the relationship between GAPDH and drugs. Results: The GAPDH was found commonly up-regulated in 24 types of human cancers and its up-regulation was significantly correlated with the poor relapse-free survival (RFS) and overall survival (OS) of BLCA, CESC, HNSC, KIRP, LIHC, and LUAD. This implies that GAPDH plays a significant role in the development of these cancers. The GAPDH up-regulation was also noticed to be associated with the different clinicopathological features of BLCA, CESC, HNSC, KIRP, LIHC, and LUAD patients. Pathway analysis has shown GAPDH involvement in different diverse pathways. Furthermore, notable correlations were observed between the expression of GAPDH and its promoter methylation level, genetic alterations, as well as the level of CD8+ T immune cells. Moreover, we identified significant regulatory drugs targeting GAPDH that have the potential to modulate its expression and potentially prevent conditions such as BLCA, CESC, HNSC, KIRP, LIHC, and LUAD. Conclusion: Based on our findings, GAPDH emerged as a promising diagnostic and prognostic biomarker for BLCA, CESC, HNSC, KIRP, LIHC, and LUAD.

The correlation between rituximab dose reduction and acute relapses of neuromyelitis optica spectrum disorder, lessons from COVID-19 epidemic

BackgroundCOVID-19 was a viral infection that led to a global pandemic in March 2020. At the beginning of the pandemic, clinicians encountered the challenge of how immunosuppressive treatments would affect the course of COVID-19 infection in people with autoimmune diseases. Neuromyelitis optica spectrum disorder is an autoimmune astrocytopathy that is caused by an inflammation in the CNS. Major treatments to prevent acute relapses include immunosuppressive drugs. Rituximab is a well-established immunosuppressive agent in NMOSD maintenance therapy. Some reports suggested that treatment with Rituximab might increase the risk of COVID-19 infection and its mortality in NMOSD. On the other hand, dose reduction or extended interval treatment might lead to acute relapses of NMOSD and permanent disability. MethodsIn this study, we evaluated the correlation between the dose of rituximab and the relapse rate of NMOSD during an epidemic. This was an observational study on 171 patients among whom 55 cases were seropositive. Some patients received full dose rituximab routinely (1000 mg/dose, every 6 months), but others were treated with half dose (500 mg/dose) during the epidemic. Also, some doses were prescribed with a delay, based on the level of CD19 and CD20. ResultsThe Pearson correlation coefficient (r) showed a negative and significant relation (r: - 0.19, p: 0.022) between the amount of drug and the number of relapses in the seropositive group, so low dosage of the drug was related to more acute relapses. In seronegative cases, there was not any valuable relationship. (p: 0.367). ConclusionLower dose of rituximab, especially in seropositive NMOSD patients, can potentially lead to acute relapses. So, the more frequent evaluation of the CD19, CD20, and, CD27 levels, and the general clinical condition of the patients should be considered.

Oral Microbiome and CPT1A Function in Fatty Acid Metabolism in Oral Cancer.

The oral microbiome is crucial for human health. Although oral dysbiosis may contribute to oral cancer (OC), the detailed relationships between the microbiome and OC remain unclear. In this case-control study, we aimed to elucidate the connection between the oral microbiome and mechanisms potentially involved in oral cancer. The study analyzed 1022 oral saliva samples, including 157 from oral cancer patients and 865 from healthy controls, using 16S ribosomal RNA (16S rRNA) sequencing and a Light Gradient Boosting Machine (LightGBM) model to identify four bacterial genera significantly associated with oral cancer. In patients with oral cancer, the relative abundance of Streptococcus and Parvimonas was higher; Corynebacterium and Prevotella showed decreased relative abundance; and levels of fatty acid oxidation enzymes, including Carnitine palmitoyltransferase 1A (CPT1A), long-chain acyl-CoA synthetase, acyl-CoA dehydrogenase, diacylglycerol choline phosphotransferase, and H+-transporting ATPase, were significantly higher compared to controls. Conversely, healthy controls exhibited increased levels of short-chain fatty acids (SCFAs) and CD4+T-helper cell counts. Survival analysis revealed that higher abundance of Streptococcus and Parvimonas, which correlated positively with interleukin-6, tumor necrosis factor-alpha, and CPT1A, were linked to poorer disease-free survival (DFS) and overall survival (OS) rates, while Prevotella and Corynebacterium were associated with better outcomes. These findings suggest that changes in these bacterial genera are associated with alterations in specific cytokines, CPT1A levels, SCFAs in oral cancer, with lower SCFA levels in patients reinforcing this link. Overall, these microbiome changes, along with cytokine and enzyme alterations, may serve as predictive markers, enhancing diagnostic accuracy for oral cancer.

Flow Cytometry Analysis of CD4⁺ and CD8⁺ T Lymphocytes in COVID- 19 Patients

The clinical presentation of COVID-19 varies greatly from case to another, with host characteristics playing a pivotal role. The immune system is a pivotal function in establishing the course of SARS-COV-2 infection. Severe instances of COVID-19 and the resulting death are caused less by the virus itself than by the destructive unrestrained immune response. Among the host determinants for poor disease prognosis is probably genetic vulnerability to dysregulated immune response. The objective of this work is to examine some of the host genetic variables that are being studied in relation to the severity of COVID-19. The complex relationship between autoimmunity and the pathophysiology of COVID-19 was examined. Patients with COVID-19 were recruited from AL-Dewaniyah Teaching Hospital and AL-Hussain Teaching Hospital in Karbala city. All patients had been diagnosed with the virus using real-time polymerase chain reaction. A total of 70 blood samples (35 from the mild group, 35 from the severe group, and 35 from the controlled group) were obtained in EDTA tubes. Orderly to investigate the correlation between the progression of disease and variations in specific regions of host immunoassays had been used by flow cytometry. The results of the flow cytometry were reported as the average percentage of positive cells for CD4 and CD8 immunological markers. Cases with COVID-19 had a substantially lower mean CD4 concentration than the healthy patients. Furthermore, the mean concentration of CD8 was significantly lower in cases with COVID-19 than in healthy. In addition, there is significant (P 0.001) decline in both CD4 and CD8 mean levels between patients with severe and mild COVID-19.

MiR-132-3p downregulates FOXO1 in CD4+ T cells and is associated with disease manifestations in patients with lupus.

This study aimed to evaluate the expression status of miR-132-3p in CD4+ T cells in patients with systemic lupus erythematosus (SLE) and explore its potential role in SLE development. The study included 60 patients with SLE and 30 healthy controls. miR-132-3p expression in CD4+ T cells was detected by real-time quantitative reverse transcription polymerase chain. Bioinformatics analyses were employed to predict target genes and explore the potential role of miR-132-3p. The associations between miR-132-3p levels and SLE Disease Activity Index (SLEDAI) score, as well as laboratory characteristics, were analyzed. miR-132-3p levels in CD4+ T cells were significantly higher in patients with SLE compared with healthy controls. Bioinformatics analysis identified FOXO1 as a potential target gene of miR-132-3p, with a particular emphasis on the FOXO signaling pathway. miR-132-3p up-regulation in CD4+ T cells was associated with high SLEDAI score, high anti-double-stranded DNA levels, low C3 and C4 levels, positive anti-ribosomal P, and high 24-hour urinary protein levels in patients with SLE. miR-132-3p may contribute to CD4+ T cell dysregulation during SLE by targeting FOXO1 and could potentially be used to assess disease severity.

Dedicator of cytokinesis 8 (DOCK8) mutation impairs the differentiation of helper T cells by regulating the glycolytic pathway of CD4+ T cells.

Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary immunodeficiency disease caused by mutations in exon 45 of the DOCK8 gene. The clinical signs primarily consist of increased serum IgE levels, eczema, repeated skin infections, allergies, and upper respiratory tract infections. Using CRISPR/Cas9 technology, we generated a DOCK8 exon 45 mutation in mice, mirroring the mutation found in patients. The results indicated that DOCK8 mutation impairs peripheral T cell homeostasis, disrupts regulatory T cells (Tregs) development, increases ICOS expression in Tregs within peripheral lymph nodes (pLn), and promotes Th17 cell differentiation within the spleen and pLn. Upon virus infection, DOCK8 mutation CD4+ T cells have a Th2 effector fate. RNA-bulk sequencing data revealed alternations in the mTOR pathway of DOCK8 mutant CD4+ T cells. We observed that DOCK8 mutation upregulates the glycolysis levels in CD4+ T cells, which is related to the Akt/mTOR/S6/HIF-1α pathway. In summary, our research elucidates that DOCK8 regulates the differentiation of helper T cells by modulating the glycolytic pathway in CD4+ T cells, thereby advancing the comprehension and offering potential treatment of diseases in DOCK8-deficient patients.

PTBP3 Mediates IL-18 Exon Skipping to Promote Immune Escape in Gallbladder Cancer.

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system, with poor response to current treatments. Abnormal alternative splicing has been associated with the development of a variety of tumors. Combining the GEO database and GBC mRNA-seq analysis, it is found high expression of the splicing factor polypyrimidine region- binding protein 3 (PTBP3) in GBC. Multi-omics analysis revealed that PTBP3 promoted exon skipping of interleukin-18 (IL-18), resulting in the expression of ΔIL-18, an isoform specifically expressed in tumors. That ΔIL-18 promotes GBC immune escape by down-regulating FBXO38 transcription levels in CD8+T cells to reduce PD-1 ubiquitin-mediated degradation is revealed. Using a HuPBMC mouse model, the role of PTBP3 and ΔIL-18 in promoting GBC growth is confirmed, and showed that an antisense oligonucleotide that blocked ΔIL-18 production displayed anti-tumor activity. Furthermore, that the H3K36me3 promotes exon skipping of IL-18 by recruiting PTBP3 via MRG15 is demonstrated, thereby coupling the processes of IL-18 transcription and alternative splicing. Interestingly, it is also found that the H3K36 methyltransferase SETD2 binds to hnRNPL, thereby interfering with PTBP3 binding to IL-18 pre-mRNA. Overall, this study provides new insights into how aberrant alternative splicing mechanisms affect immune escape, and provides potential new perspectives for improving GBC immunotherapy.

Cytokine Profile in Children Following SARS-CoV-2 Infection: Preliminary Findings.

We provide preliminary evidence that, also in children, Long coronavirus disease (COVID) may be characterized by a proinflammatory signature. Ten Long COVID patients, 7 convalescent subjects after COVID infection and 4 healthy controls were enrolled. When adjusted for sex, children with long COVID had statistically significant differences in the levels of Flt3L, CD5, uPA, CCL23, CD40 and TGFα. When adjusted for age, CCL23 levels remained statistically significant.

Insights in AAV-mediated antigen-specific immunity and a strategy for AAV vaccine dose reduction through AAV-extracellular vesicle association

We previously showed therapeutic advantages of using a capsid-modified and encoded antigen-optimized AAV-based cancer vaccine to initiate strong antigen-specific immune responses and increase survival in a syngeneic mouse model of melanoma. In the current study, we further explore AAV vaccine dose reduction and possible mechanisms of the immune response. Immunization with extracellular vesicle (EV)-associated AAV6-S663V encoded ovalbumin (OVA) or tyrosinase-related protein 1 (TRP-1) induced significantly higher levels of antigen-specific CD8+ T cells compared to standard AAV in mice. Importantly, a higher number of specific CD8+ T cells was achieved with EV-AAV several logs lower than optAAV-based doses. EV-optAAV-OVA was used in a dose of 100-times lower, and EV-optTRP-1 10-times lower than optOVA and optTRP-1 correspondingly. Our data suggest that significant dose reduction for optimized AAV-based vaccines is possible without sacrificing efficiency. Additionally, we studied the role of conventional type 1 dendritic cells (cDC1) in optimized AAV-based immunization using a C57BL/6-Irf8em1Kmm (Irf8+32-/-) mouse model lacking cDC1. Interestingly, we found that cDC1 are not essential for conveying effector T cell responses to AAV-encoded tumor antigens.

Clinical significance and therapeutic implication of CD200 in pancreatic cancer

BackgroundCD200, a negative regulator of T cells as well as a marker for cancer stem cells, represents a significant prognostic factor and potential therapeutic target in certain cancers. However, its clinical significance remains unknown in pancreatic ductal adenocarcinoma (PDAC). MethodsCD200 was assessed in 220 resected PDAC patients who underwent surgery with or without neoadjuvant chemoradiotherapy (NACRT). We examined the clinicopathological outcomes associated with CD200 and further assessed its clinical implications regarding immunological and cancer stem cell properties. ResultsNACRT was associated with higher CD200 expression (66.4 % vs. 32.2 %, P < 0.001) compared to upfront surgery. CD200 was identified as an independent poor prognostic factor in NACRT (hazard ratio 1.90, 95 % confidence interval 1.12–3.23, P = 0.016), but not in upfront surgery patients. Post-recurrence survival was significantly worse in CD200+ patients compared to CD200- patients in the NACRT group, but there was no significant difference observed in the upfront surgery group. CD200 expression was correlated with significantly lower levels of CD4+, CD8+, and CD45RO+ tumor-infiltrating lymphocytes. Furthermore, the correlation of CD200 with pancreatic cancer stem cell markers CD44/CD24/ESA was stronger in irradiated human pancreatic cancer cells. ConclusionsOur data underscore novel roles for CD200 in immune evasion as well as therapy resistance in pancreatic cancer. CD200 may represent a novel poor prognostic predictive factor and potential therapeutic target for PDAC with NACRT.

Hyperactive Dendritc Cells Redirect Aged Antitumor Immunity.

Aging is one of the biggest risk factors for cancer development. More than 85% of all cancers occur in individuals above 55 years old, often accompanied by age-associated immune defects. Previous studies on the tumor microenvironment during aging have identified several factors, such as the roles of fibroblasts, immunosuppression, and metastasis. However, the aging-associated defects in antitumor immunity, particularly with regard to T cells, remain underexplored. Recent findings by Zhivaki and colleagues suggest that age-related immune defects affecting antitumor responses involve reduced levels of CD8+ T cells and compromised dendritic cell (DC) functions such as antigen presentation and migration. Their study demonstrates that a hyperactive DC vaccine can restore DC functions in older mice. Furthermore, these hyperactive DCs, characterized by increased IL1β production and better migratory capability to the lymph node, promote the development of cytolytic CD4+ T cells exhibiting Th1-like phenotypes. This research reveals mechanisms underlying the response to hyperactive DC vaccines in older mice and highlights the critical role of cytolytic CD4+ T cells as substitutes for CD8+ T cells in driving antitumor immunity and achieving long-term tumor control in older mice.