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Frontiers in Immunology 2024Anoikis is a form of programmed cell death essential for preventing cancer metastasis. In some solid cancer, anoikis resistance can facilitate tumor progression....
BACKGROUND
Anoikis is a form of programmed cell death essential for preventing cancer metastasis. In some solid cancer, anoikis resistance can facilitate tumor progression. However, this phenomenon is underexplored in clear-cell renal cell carcinoma (ccRCC).
METHODS
Using SVM machine learning, we identified core anoikis-related genes (ARGs) from ccRCC patient transcriptomic data. A LASSO Cox regression model stratified patients into risk groups, informing a prognostic model. GSVA and ssGSEA assessed immune infiltration, and single-cell analysis examined ARG expression across immune cells. Quantitative PCR and immunohistochemistry validated ARG expression differences between immune therapy responders and non-responders in ccRCC.
RESULTS
ARGs such as CCND1, CDKN3, PLK1, and BID were key in predicting ccRCC outcomes, linking higher risk with increased Treg infiltration and reduced M1 macrophage presence, indicating an immunosuppressive environment facilitated by anoikis resistance. Single-cell insights showed ARG enrichment in Tregs and dendritic cells, affecting immune checkpoints. Immunohistochemical analysis reveals that ARGs protein expression is markedly elevated in ccRCC tissues responsive to immunotherapy.
CONCLUSION
This study establishes a novel anoikis resistance gene signature that predicts survival and immunotherapy response in ccRCC, suggesting that manipulating the immune environment through these ARGs could improve therapeutic strategies and prognostication in ccRCC.
Topics: Humans; Carcinoma, Renal Cell; Anoikis; Kidney Neoplasms; Single-Cell Analysis; Prognosis; Gene Expression Regulation, Neoplastic; Drug Resistance, Neoplasm; Tumor Microenvironment; Lymphocytes, Tumor-Infiltrating; Transcriptome; Cell Line, Tumor; Biomarkers, Tumor; T-Lymphocytes, Regulatory; Gene Expression Profiling; Male; Multiomics
PubMed: 38953023
DOI: 10.3389/fimmu.2024.1427475 -
Frontiers in Immunology 2024More than 350,000 chemicals make up the chemical universe that surrounds us every day. The impact of this vast array of compounds on our health is still poorly...
INTRODUCTION
More than 350,000 chemicals make up the chemical universe that surrounds us every day. The impact of this vast array of compounds on our health is still poorly understood. Manufacturers are required to carry out toxicological studies, for example on the reproductive or nervous systems, before putting a new substance on the market. However, toxicological safety does not exclude effects resulting from chronic exposure to low doses or effects on other potentially affected organ systems. This is the case for the microbiome-immune interaction, which is not yet included in any safety studies.
METHODS
A high-throughput in vitro model was used to elucidate the potential effects of environmental chemicals and chemical mixtures on microbiome-immune interactions. Therefore, a simplified human intestinal microbiota (SIHUMIx) consisting of eight bacterial species was cultured in a bioreactor that partially mimics intestinal conditions. The bacteria were continuously exposed to mixtures of representative and widely distributed environmental chemicals, i.e. bisphenols (BPX) and/or per- and polyfluoroalkyl substances (PFAS) at concentrations of 22 µM and 4 µM, respectively. Furthermore, changes in the immunostimulatory potential of exposed microbes were investigated using a co-culture system with human peripheral blood mononuclear cells (PBMCs).
RESULTS
The exposure to BPX, PFAS or their mixture did not influence the community structure and the riboflavin production of SIHUMIx . However, it altered the potential of the consortium to stimulate human immune cells: in particular, activation of CD8 MAIT cells was affected by the exposure to BPX- and PFAS mixtures-treated bacteria.
DISCUSSION
The present study provides a model to investigate how environmental chemicals can indirectly affect immune cells via exposed microbes. It contributes to the much-needed knowledge on the effects of EDCs on an organ system that has been little explored in this context, especially from the perspective of cumulative exposure.
Topics: Humans; Gastrointestinal Microbiome; Phenols; Benzhydryl Compounds; Fluorocarbons; Leukocytes, Mononuclear; Coculture Techniques; Environmental Pollutants; Bacteria
PubMed: 38953021
DOI: 10.3389/fimmu.2024.1298971 -
Molecular Cancer Jun 2024Natural killer (NK) cells are important immune cells in the organism and are the third major type of lymphocytes besides T cells and B cells, which play an important... (Review)
Review
Natural killer (NK) cells are important immune cells in the organism and are the third major type of lymphocytes besides T cells and B cells, which play an important function in cancer therapy. In addition to retaining the tumor cell killing function of natural killer cells, natural killer cell-derived exosomes cells also have the characteristics of high safety, wide source, easy to preserve and transport. At the same time, natural killer cell-derived exosomes are easy to modify, and the engineered exosomes can be used in combination with a variety of current cancer therapies, which not only enhances the therapeutic efficacy, but also significantly reduces the side effects. Therefore, this review summarizes the source, isolation and modification strategies of natural killer cell-derived exosomes and the combined application of natural killer cell-derived engineered exosomes with other antitumor therapies, which is expected to accelerate the clinical translation process of natural killer cell-derived engineered exosomes in cancer therapy.
Topics: Humans; Exosomes; Killer Cells, Natural; Neoplasms; Animals; Clinical Relevance
PubMed: 38951879
DOI: 10.1186/s12943-024-02045-4 -
Journal of Translational Medicine Jul 2024The spatial context of tumor-infiltrating immune cells (TIICs) is important in predicting colorectal cancer (CRC) patients' clinical outcomes. However, the prognostic...
BACKGROUND
The spatial context of tumor-infiltrating immune cells (TIICs) is important in predicting colorectal cancer (CRC) patients' clinical outcomes. However, the prognostic value of the TIIC spatial distribution is unknown. Thus, we aimed to investigate the association between TIICs in situ and patient prognosis in a large CRC sample.
METHODS
We implemented multiplex immunohistochemistry staining technology in 190 CRC samples to quantify 14 TIIC subgroups in situ. To delineate the spatial relationship of TIICs to tumor cells, tissue slides were segmented into tumor cell and microenvironment compartments based on image recognition technology, and the distance between immune and tumor cells was calculated by implementing the computational pipeline phenoptr.
RESULTS
MPO neutrophils and CD68IDO1 tumor-associated macrophages (TAMs) were enriched in the epithelial compartment, and myeloid lineage cells were located nearest to tumor cells. Except for CD68CD163 TAMs, other cells were all positively associated with favorable prognosis. The prognostic predictive power of TIICs was highly related to their distance to tumor cells. Unsupervised clustering analysis divided colorectal cancer into three subtypes with distinct prognostic outcomes, and correlation analysis revealed the synergy among B cells, CD68IDO1TAMs, and T lineage cells in producing an effective immune response.
CONCLUSIONS
Our study suggests that the integration of spatial localization with TIIC abundance is important for comprehensive prognostic assessment.
Topics: Humans; Colorectal Neoplasms; Prognosis; Male; Female; Middle Aged; Tumor Microenvironment; Cluster Analysis; Aged; Lymphocytes, Tumor-Infiltrating; Immunohistochemistry; Macrophages; Spatial Analysis
PubMed: 38951801
DOI: 10.1186/s12967-024-05418-x -
BMC Cancer Jun 2024The cardiotoxicity related to 5-Fluorouracil (5-FU) in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been...
BACKGROUND AND AIMS
The cardiotoxicity related to 5-Fluorouracil (5-FU) in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been identified as a novel predictive marker for the development of cardiovascular illnesses in individuals without pre-existing health conditions. However, it remains unclear whether the levels of SII are linked to cardiotoxicity related to 5-FU. This retrospective study aims to fill this knowledge gap by examining the correlation between SII and cardiotoxicity related to 5-FU in a colorectal cancer cohort.
METHODS
The study comprised colorectal cancer patients who received 5-FU-based chemotherapy at the affiliated cancer hospital of Guizhou Medical University between January 1, 2018 and December 31, 2020. After adjustment for confounders and stratification by tertiles of the interactive factor, linear regression analyses, curve fitting and threshold effect analyses were conducted.
RESULTS
Of the 754 patients included final analysis, approximately 21% (n = 156) of them ultimately experienced cardiotoxicity related to 5-FU. Monocytes (M) was found as an influential element in the interaction between SII and cardiotoxicity related to 5-FU. In the low tertile of M (T1: M ≤ 0.38 × 10/L), increasing log SII was positively correlated with cardiotoxicity related to 5-FU (Odds Ratio [OR], 8.04; 95% confidence interval [95%CI], 1.68 to 38.56). However, a curvilinear relationship between log SII and cardiotoxicity was observed in the middle tertile of M (T2: 0.38 < M ≤ 0.52 × 10/L). An increase in log SII above 1.37 was shown to be associated with a decreased risk of cardiotoxicity (OR, 0.14; 95%CI, 0.02 to 0.88), indicating a threshold effect. In the high tertile of M (T3: M > 0.52 × 10/L), there was a tendency towards a negative linear correlation between the log SII and cardiotoxicity was observed (OR, 0.85; 95%CI, 0.37 to 1.98).
CONCLUSION
Our findings suggest that SII may serve as a potential biomarker for predicting cardiotoxicity related to 5-FU in colorectal cancer patients. SII is an independent risk factor for cardiotoxicity related to 5-FU with low monocytes levels (T1). Conversely, in the middle monocytes levels (T2), SII is a protective factor for cardiotoxicity related to 5-FU but with a threshold effect.
Topics: Humans; Fluorouracil; Colorectal Neoplasms; Male; Female; Middle Aged; Cardiotoxicity; Retrospective Studies; Aged; Inflammation; Antimetabolites, Antineoplastic; Monocytes; Adult
PubMed: 38951749
DOI: 10.1186/s12885-024-12568-0 -
Scientific Reports Jul 2024The NK cell is an important component of the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC), also plays a significant role in PDAC development. This...
The NK cell is an important component of the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC), also plays a significant role in PDAC development. This study aimed to explore the relationship between NK cell marker genes and prognosis, immune response of PDAC patients. By scRNA-seq data, we found the proportion of NK cells were significantly downregulated in PDAC and 373 NK cell marker genes were screened out. By TCGA database, we enrolled 7 NK cell marker genes to construct the signature for predicting prognosis in PDAC patients. Cox analysis identified the signature as an independent factor for pancreatic cancer. Subsequently, the predictive power of signature was validated by 6 GEO datasets and had an excellent evaluation. Our analysis of relationship between the signature and patients' immune status revealed that the signature has a strong correlation with immunocyte infiltration, inflammatory reaction, immune checkpoint inhibitors (ICIs) response. The NK cell marker genes are closely related to the prognosis and immune capacity of PDAC patients, and they have potential value as a therapeutic target.
Topics: Humans; Carcinoma, Pancreatic Ductal; Killer Cells, Natural; Prognosis; Pancreatic Neoplasms; Biomarkers, Tumor; Single-Cell Analysis; Female; Male; Gene Expression Regulation, Neoplastic; Sequence Analysis, RNA; Tumor Microenvironment; Middle Aged; Aged; Gene Expression Profiling
PubMed: 38951569
DOI: 10.1038/s41598-024-65917-1 -
The Journal of Clinical Investigation Apr 2024Ectopic lymphoid structures (ELSs) in the rheumatoid synovial joints sustain autoreactivity against locally expressed autoantigens. We recently identified recombinant...
Ectopic lymphoid structures (ELSs) in the rheumatoid synovial joints sustain autoreactivity against locally expressed autoantigens. We recently identified recombinant monoclonal antibodies (RA-rmAbs) derived from single, locally differentiated rheumatoid arthritis (RA) synovial B cells, which specifically recognize fibroblast-like synoviocytes (FLSs). Here, we aimed to identify the specificity of FLS-derived autoantigens fueling local autoimmunity and the functional role of anti-FLS antibodies in promoting chronic inflammation. A subset of anti-FLS RA-rmAbs reacting with a 60 kDa band from FLS extracts demonstrated specificity for HSP60 and partial cross-reactivity to other stromal autoantigens (i.e., calreticulin/vimentin) but not to citrullinated fibrinogen. Anti-FLS RA-rmAbs, but not anti-neutrophil extracellular traps rmAbs, exhibited pathogenic properties in a mouse model of collagen-induced arthritis. In patients, anti-HSP60 antibodies were preferentially detected in RA versus osteoarthritis (OA) synovial fluid. Synovial HSPD1 and CALR gene expression analyzed using bulk RNA-Seq and GeoMx-DSP closely correlated with the lympho-myeloid RA pathotype, and HSP60 protein expression was predominantly observed around ELS. Moreover, we observed a significant reduction in synovial HSP60 gene expression followed B cell depletion with rituximab that was strongly associated with the treatment response. Overall, we report that synovial stromal-derived autoantigens are targeted by pathogenic autoantibodies and are associated with specific RA pathotypes, with potential value for patient stratification and as predictors of the response to B cell-depleting therapies.
Topics: Arthritis, Rheumatoid; Animals; Humans; Mice; Autoantigens; Germinal Center; Chaperonin 60; Autoantibodies; Autoimmunity; Male; Synoviocytes; Arthritis, Experimental; Female; B-Lymphocytes; Tertiary Lymphoid Structures
PubMed: 38950333
DOI: 10.1172/JCI169754 -
The Journal of Clinical Investigation Jul 2024
Topics: Humans; Killer Cells, Natural; Animals; Glucuronidase; Immunologic Surveillance; Neoplasm Invasiveness; Mice; Neoplasms
PubMed: 38949030
DOI: 10.1172/JCI183295 -
The Journal of Clinical Investigation Jul 2024
Topics: T-Lymphocytes, Regulatory; Humans; Receptors, Immunologic; Animals; Mice
PubMed: 38949028
DOI: 10.1172/JCI183278 -
The Journal of Clinical Investigation Jul 2024Type 3 innate lymphoid cells (ILC3s) are key regulators of intestinal homeostasis and epithelial barrier integrity. In this issue of the JCI, Cao and colleagues found...
Type 3 innate lymphoid cells (ILC3s) are key regulators of intestinal homeostasis and epithelial barrier integrity. In this issue of the JCI, Cao and colleagues found that a sensor of endoplasmic reticulum (ER) stress, the inositol-requiring kinase 1α/X-box-binding protein 1 (IRE1α/XBP1) pathway, fine-tuned the functions of ILC3s. Activation of IRE1α and XBP1 in ILC3s limited intestinal inflammation in mice and correlated with the efficacy of ustekinumab, an IL-12/IL-23 blocker, in patients with Crohn's disease. These results advance our understanding in the use of ILCs as biomarkers not only to predict disease outcomes but also to indicate the response to biologicals in patients with inflammatory bowel disease.
Topics: X-Box Binding Protein 1; Animals; Endoribonucleases; Protein Serine-Threonine Kinases; Humans; Mice; Endoplasmic Reticulum Stress; Lymphocytes; Signal Transduction; Crohn Disease; Immunity, Innate; Inflammation
PubMed: 38949019
DOI: 10.1172/JCI182204