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World Journal of Surgical Oncology Jun 2024The alteration of the immune microenvironment in the axillary metastatic lymph nodes of luminal A breast cancer patients is still unclear.
BACKGROUND
The alteration of the immune microenvironment in the axillary metastatic lymph nodes of luminal A breast cancer patients is still unclear.
METHODS
Postsurgical tissues from the enrolled luminal A BCs were divided into five categories: primary BC lesion at stage N0 (PL1), primary BC lesion at stage N1 (PL2), negative axillary lymph node at stage N0 BC (LN1), negative axillary lymph node at stage N1 BC (LN2), and positive axillary lymph node at stage N1 BC (LN3). The frequencies of positive immune markers (CD4, CD8, PD1, PD-L1, T-cell immunoglobulin and mucin domain 3 (TIM3), and forkhead box protein 3 (Foxp3)) in the above tissues were quantified by AKOYA Opal Polaris 7 Color Manual IHC Detection Kit.
RESULTS
A total of 50 female patients with luminal A BC were enrolled in this study. Among these patients, 23 had stage N1 disease, and 27 had stage N0 disease. Compared with that in the PL2 subgroup, the frequency of PD-1-positive cells was significantly greater in the PL1 subgroup, whether at the stromal or intratumoral level (P value < 0.05). Both the frequency of CD8 + T cells in LN1 and that in LN2 were significantly greater than that in LN3 (P value < 0.05). The frequency of TIM3 + T cells in LN1 was significantly greater than that in PL1 (P value < 0.05). The frequency of CD8 + TIM3 + T cells was significantly greater in both the LN2 and LN3 groups than in the PL2 group (P value < 0.05). The frequency of CD4 + Foxp3 + T cells was significantly greater in LN1 than in PL1 (P value < 0.05), which was the same for both LN3 and PL2 (P value < 0.05).
CONCLUSION
Increased frequencies of CD8 + PD1+, CD8 + TIM3 + and CD4 + Foxp3 + T cells might inhibit the immune microenvironment of axillary metastatic lymph nodes in luminal A breast cancer patients and subsequently promote lymph node metastasis.
Topics: Humans; Female; Breast Neoplasms; Tumor Microenvironment; Middle Aged; Lymphatic Metastasis; Axilla; Lymph Nodes; Adult; Prognosis; Biomarkers, Tumor; Aged; Follow-Up Studies; Neoplasm Staging; Lymphocytes, Tumor-Infiltrating; B7-H1 Antigen; Programmed Cell Death 1 Receptor
PubMed: 38937736
DOI: 10.1186/s12957-024-03454-x -
Scientific Reports Jun 2024There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory...
There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory cells. We characterized the specific distribution of myeloid cells of both human type A AAD samples and a murine AAD model generated using angiotensin II (ANGII) and β-aminopropionitrile (BAPN) by single-cell RNA sequencing (scRNA-seq). We also examined the effect of an anti-interleukin-1β (IL-1β) antibody in the murine AAD model. IL1B inflammatory macrophages and classical monocytes were increased in human AAD samples. Trajectory analysis demonstrated that IL1B inflammatory macrophages differentiated from S100A8/9/12 classical monocytes uniquely observed in the aorta of AAD. We found increased infiltration of neutrophils and monocytes with the expression of inflammatory cytokines in the aorta and accumulation of inflammatory macrophages before the onset of macroscopic AAD in the murine AAD model. In blocking experiments using an anti-IL-1β antibody, it improved survival of murine AAD model by preventing elastin degradation. We observed the accumulation of inflammatory macrophages expressing IL-1β in both human AAD samples and in a murine AAD model. Anti-IL-1β antibody could improve the mortality rate in mice, suggesting that it may be a treatment option for AAD.
Topics: Aortic Dissection; Interleukin-1beta; Animals; Humans; Macrophages; Mice; Disease Models, Animal; Male; Aminopropionitrile; Angiotensin II; Inflammation; Monocytes; Aorta; Mice, Inbred C57BL; Female
PubMed: 38937528
DOI: 10.1038/s41598-024-65931-3 -
Communications Biology Jun 2024Distinct Natural Killer (NK)-like CD57 and PD-1 CD8 exhausted-like T cell populations (Tex) have both been linked to beneficial immunotherapy response in autoimmune type...
Distinct Natural Killer (NK)-like CD57 and PD-1 CD8 exhausted-like T cell populations (Tex) have both been linked to beneficial immunotherapy response in autoimmune type 1 diabetes (T1D) patients. The origins and relationships between these cell types are poorly understood. Here we show that while PD-1 and CD57 Tex populations are epigenetically similar, CD57 Tex cells display unique increased chromatin accessibility of inhibitory Killer Cell Immunoglobulin-like Receptor (iKIR) and other NK cell genes. PD-1 and CD57 Tex also show reciprocal expression of Inhibitory Receptors (IRs) and iKIRs accompanied by chromatin accessibility of Tcf1 and Tbet transcription factor target sites, respectively. CD57 Tex show unappreciated gene expression heterogeneity and share clonal relationships with PD-1 Tex, with these cells differentiating along four interconnected lineage trajectories: Tex-PD-1, Tex-CD57, Tex-Branching, and Tex-Fluid. Our findings demonstrate new relationships between Tex-like populations in human autoimmune disease and suggest that modulating common precursor populations may enhance response to autoimmune disease treatment.
Topics: Diabetes Mellitus, Type 1; Humans; CD8-Positive T-Lymphocytes; Killer Cells, Natural; Programmed Cell Death 1 Receptor; CD57 Antigens; Cell Lineage; Hepatocyte Nuclear Factor 1-alpha; Female; Male; Adult
PubMed: 38937521
DOI: 10.1038/s42003-024-06456-3 -
Nature Communications Jun 2024Neutrophils are increasingly implicated in chronic inflammation and metabolic disorders. Here, we show that visceral adipose tissue (VAT) from individuals with obesity...
Neutrophils are increasingly implicated in chronic inflammation and metabolic disorders. Here, we show that visceral adipose tissue (VAT) from individuals with obesity contains more neutrophils than in those without obesity and is associated with a distinct bacterial community. Exploring the mechanism, we gavaged microbiome-depleted mice with stool from patients with and without obesity during high-fat or normal diet administration. Only mice receiving high-fat diet and stool from subjects with obesity show enrichment of VAT neutrophils, suggesting donor microbiome and recipient diet determine VAT neutrophilia. A rise in pro-inflammatory CD4+ Th1 cells and a drop in immunoregulatory T cells in VAT only follows if there is a transient spike in neutrophils. Human VAT neutrophils exhibit a distinct gene expression pattern that is found in different human tissues, including tumors. VAT neutrophils and bacteria may be a novel therapeutic target for treating inflammatory-driven complications of obesity, including insulin resistance and colon cancer.
Topics: Intra-Abdominal Fat; Animals; Obesity; Humans; Neutrophils; Diet, High-Fat; Mice; Inflammation; Gastrointestinal Microbiome; Male; Mice, Inbred C57BL; Female; Feces; Microbiota; Th1 Cells; Neutrophil Infiltration
PubMed: 38937454
DOI: 10.1038/s41467-024-48935-5 -
Nature Communications Jun 2024Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor...
Although patients benefit from immune checkpoint inhibition (ICI) therapy in a broad variety of tumors, resistance may arise from immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, OVs could potentially restore ICI responsiveness via recruitment, priming, and activation of anti-tumor T cells. Here we find that on the contrary, an oncolytic vesicular stomatitis virus, expressing interferon-ß (VSV-IFNß), antagonizes the effect of anti-PD-L1 therapy in a partially anti-PD-L1-responsive model of HCC. Cytometry by Time of Flight shows that VSV-IFNß expands dominant anti-viral effector CD8 T cells with concomitant relative disappearance of anti-tumor T cell populations, which are the target of anti-PD-L1. However, by expressing a range of HCC tumor antigens within VSV, combination OV and anti-PD-L1 therapeutic benefit could be restored. Our data provide a cautionary message for the use of highly immunogenic viruses as tumor-specific immune-therapeutics by showing that dominant anti-viral T cell responses can inhibit sub-dominant anti-tumor T cell responses. However, through encoding tumor antigens within the virus, oncolytic virotherapy can generate anti-tumor T cell populations upon which immune checkpoint blockade can effectively work.
Topics: Oncolytic Viruses; Animals; Oncolytic Virotherapy; Carcinoma, Hepatocellular; Tumor Microenvironment; Mice; B7-H1 Antigen; Humans; Liver Neoplasms; Antigens, Neoplasm; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Interferon-beta; Mice, Inbred C57BL; Immune Checkpoint Inhibitors; T-Lymphocytes; Female; Vesiculovirus
PubMed: 38937436
DOI: 10.1038/s41467-024-49286-x -
Redox Biology Jun 2024The effects of low energy availability (LEA) on the immune system are poorly understood. This study examined the effects of 14 days of LEA on immune cell redox balance...
INTRODUCTION
The effects of low energy availability (LEA) on the immune system are poorly understood. This study examined the effects of 14 days of LEA on immune cell redox balance and inflammation at rest and in response to acute exercise, and exercise performance in female athletes.
METHODS
Twelve female endurance athletes (age: 26.8 ± 3.4 yrs, maximum oxygen uptake (V˙O): 55.2 ± 5.1 mL × min × kg) were included in a randomized, single-blinded crossover study. They were allocated to begin with either 14 days of optimal energy availability diet (OEA, 52 ± 2 kcal × kg fat free mass (FFM) × day) or LEA diet (22 ± 2 kcal × kg FFM × day), followed by 3 days of refueling (OEA) with maintained training volume. Peripheral blood mononuclear cells (PBMCs) were isolated, and plasma obtained at rest before and after each dietary period. The PBMCs were used for analysis of mitochondrial respiration and HO emission and specific proteins. Exercise performance was assessed on cycle by a 20-min time trial and time to exhaustion at an intensity corresponding to ∼110 % V˙O).
RESULTS
LEA was associated with a 94 % (P = 0.003) increase in PBMC NADPH oxidase 2 protein content, and a 22 % (P = 0.013) increase in systemic cortisol. LEA also caused an alteration of several inflammatory related proteins (P < 0.05). Acute exercise augmented HO emission in PBMCs (P < 0.001) following both OEA and LEA, but to a greater extent following LEA. LEA also reduced the mobilization of white blood cells with acute exercise. After LEA, performance was reduced in both exercise tests (P < 0.001), and the reduced time trial performance remained after the 3 days of refueling (P < 0.001).
CONCLUSION
14 days of LEA in female athletes increased cortisol levels and had a pronounced effect on the immune system, including increased capacity for ROS production, altered plasma inflammatory proteome and lowered exercise induced mobilization of leukocytes. Furthermore, LEA resulted in a sustained impairment in exercise performance.
PubMed: 38936255
DOI: 10.1016/j.redox.2024.103250 -
Emerging Microbes & Infections Dec 2024Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral...
Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (= 0.048) and 96 (= 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010-37.377; = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770). ClinicalTrials.gov identifier: NCT04098770. ClinicalTrials.gov identifier: NCT02651376.
Topics: Humans; Male; Female; Adult; Middle Aged; Immunotherapy, Adoptive; Immunocompromised Host; HLA Antigens; Acquired Immunodeficiency Syndrome; Treatment Outcome; AIDS-Related Opportunistic Infections; Transplantation, Homologous; CD4-Positive T-Lymphocytes; CD4 Lymphocyte Count
PubMed: 38935839
DOI: 10.1080/22221751.2024.2364744 -
Clinical and Translational Medicine Jul 2024Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis,... (Review)
Review
Hepatitis B virus (HBV) infection playsa significant role in the etiology and progression of liver-relatedpathologies, encompassing chronic hepatitis, fibrosis, cirrhosis, and eventual hepatocellularcarcinoma (HCC). Notably, HBV infection stands as the primary etiologicalfactor driving the development of HCC. Given the significant contribution ofHBV infection to liver diseases, a comprehensive understanding of immunedynamics in the liver microenvironment, spanning chronic HBV infection,fibrosis, cirrhosis, and HCC, is essential. In this review, we focused on thefunctional alterations of CD8 T cells within the pathogenic livermicroenvironment from HBV infection to HCC. We thoroughly reviewed the roles ofhypoxia, acidic pH, metabolic reprogramming, amino acid deficiency, inhibitory checkpointmolecules, immunosuppressive cytokines, and the gut-liver communication in shapingthe dysfunction of CD8 T cells in the liver microenvironment. Thesefactors significantly impact the clinical prognosis. Furthermore, we comprehensivelyreviewed CD8 T cell-based therapy strategies for liver diseases,encompassing HBV infection, fibrosis, cirrhosis, and HCC. Strategies includeimmune checkpoint blockades, metabolic T-cell targeting therapy, therapeuticT-cell vaccination, and adoptive transfer of genetically engineered CD8 T cells, along with the combined usage of programmed cell death protein-1/programmeddeath ligand-1 (PD-1/PD-L1) inhibitors with mitochondria-targeted antioxidants.Given that targeting CD8 T cells at various stages of hepatitis Bvirus-induced hepatocellular carcinoma (HBV + HCC) shows promise, we reviewedthe ongoing need for research to elucidate the complex interplay between CD8 T cells and the liver microenvironment in the progression of HBV infection toHCC. We also discussed personalized treatment regimens, combining therapeuticstrategies and harnessing gut microbiota modulation, which holds potential forenhanced clinical benefits. In conclusion, this review delves into the immunedynamics of CD8 T cells, microenvironment changes, and therapeuticstrategies within the liver during chronic HBV infection, HCC progression, andrelated liver diseases.
Topics: Humans; CD8-Positive T-Lymphocytes; Hepatitis B virus; Hepatitis B, Chronic; Carcinoma, Hepatocellular; Liver Neoplasms; Liver Diseases
PubMed: 38935536
DOI: 10.1002/ctm2.1731 -
Frontiers in Immunology 2024Triple-negative breast cancer (TNBC) is a subtype of breast cancer that presents significant therapeutic challenges due to the absence of estrogen receptor (ER),... (Review)
Review
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that presents significant therapeutic challenges due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. As a result, conventional hormonal and targeted therapies are largely ineffective, underscoring the urgent need for novel treatment strategies. γδT cells, known for their robust anti-tumor properties, show considerable potential in TNBC treatment as they can identify and eliminate tumor cells without reliance on MHC restrictions. These cells demonstrate extensive proliferation both and , and can directly target tumors through cytotoxic effects or indirectly by promoting other immune responses. Studies suggest that expansion and adoptive transfer strategies targeting Vδ2 and Vδ1 γδT cell subtypes have shown promise in preclinical TNBC models. This review compiles and discusses the existing literature on the primary subgroups of γδT cells, their roles in cancer therapy, their contributions to tumor cell cytotoxicity and immune modulation, and proposes potential strategies for future γδT cell-based immunotherapies in TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Animals; Female; Receptors, Antigen, T-Cell, gamma-delta; Intraepithelial Lymphocytes; Immunotherapy, Adoptive; Immunotherapy
PubMed: 38933280
DOI: 10.3389/fimmu.2024.1420107 -
Frontiers in Immunology 2024Bispecific antibodies (BsAbs) can simultaneously target two epitopes of different antigenic targets, bringing possibilities for diversity in antibody drug design and are...
INTRODUCTION
Bispecific antibodies (BsAbs) can simultaneously target two epitopes of different antigenic targets, bringing possibilities for diversity in antibody drug design and are promising tools for the treatment of cancers and other diseases. T-cell engaging bsAb is an important application of the bispecific antibody, which could promote T cell-mediated tumor cell killing by targeting tumor-associated antigen (TAA) and CD3 at the same time.
METHODS
This study comprised antibodies purification, Elisa assay for antigen binding, cytotoxicity assays, T cell activation by flow cytometry and xenogenic tumor model .
RESULTS
We present a novel bsAb platform named PHE-Ig technique to promote cognate heavy chain (HC)-light chain (LC) pairing by replacing the CH1/CL regions of different monoclonal antibodies (mAbs) with the natural A and B chains of PHE1 fragment of Integrin β2 based on the knob-in-hole (KIH) technology. We had also verified that PHE-Ig technology can be effectively used as a platform to synthesize different desired bsAbs for T-cell immunotherapy. Especially, BCMA×CD3 PHE-Ig bsAbs exhibited robust anti-multiple myeloma (MM) activity and .
DISCUSSION
Moreover, PHE1 domain was further shortened with D14G and R41S mutations, named PHE-S, and the PHE-S-based BCMA×CD3 bsAbs also showed anti BCMA tumor effect and , bringing more possibilities for the development and optimization of different bsAbs. To sum up, PHE1-based IgG-like antibody platform for bsAb construction provides a novel strategy for enhanced T-cell immunotherapy.
Topics: Antibodies, Bispecific; Animals; Humans; T-Lymphocytes; Mice; Immunoglobulin G; Immunotherapy; Cell Line, Tumor; Multiple Myeloma; Xenograft Model Antitumor Assays; Lymphocyte Activation; CD3 Complex; Antigens, Neoplasm
PubMed: 38933272
DOI: 10.3389/fimmu.2024.1415834