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Cancer Epidemiology, Biomarkers &... Jul 2024African Americans have higher incidence and mortality from lung cancer than non-Hispanic Whites, but investigations into differences in immune response have been...
BACKGROUND
African Americans have higher incidence and mortality from lung cancer than non-Hispanic Whites, but investigations into differences in immune response have been minimal. Therefore, we compared components of the tumor microenvironment among African Americans and non-Hispanic Whites diagnosed with non-small cell lung cancer (NSCLC) based on PD-L1 or tertiary lymphoid structure (TLS) status to identify differences of translational relevance.
METHODS
Using a cohort of 280 NSCLC patients from the INHALE study (non-Hispanic White: n=155; African American: n=125), we evaluated PD-L1 tumor proportion score (<1% vs. ≥1%) and TLS status (presence/absence), comparing differences within the tumor microenvironment based on immune cell distribution and differential expression of genes.
RESULTS
Tumors from African Americans had a higher proportion of plasma cell signatures within the tumor microenvironment than non-Hispanic Whites. In addition, gene expression patterns in African American PD-L1 positive samples suggest these tumors contained greater numbers of γδ T-cells and resting dendritic cells, along with fewer CD8+ T-cells after adjusting for age, sex, pack-years, stage, and histology. Investigation of differential expression of B-cell/plasma cell related genes between the two patient populations revealed that two immunoglobulin genes (IGKV2-29 and IGLL5) were associated with decreased mortality risk in African Americans.
CONCLUSIONS
In the first known race-stratified analysis of tumor microenvironment components in lung cancer based on PD-L1 expression or TLS status, differences within the immune cell composition and transcriptomic signature were identified that may have therapeutic implications.
IMPACT
Future investigation of racial variation within the tumor microenvironment may help direct the use of immunotherapy.
PubMed: 38953893
DOI: 10.1158/1055-9965.EPI-24-0333 -
International Immunology Jul 2024Dendritic cells (DCs) are specialized antigen-presenting cells for lymphocytes, including regulatory T (Treg) cells, a subset of CD4+ T cells expressing CD25 and Foxp3,...
Dendritic cells (DCs) are specialized antigen-presenting cells for lymphocytes, including regulatory T (Treg) cells, a subset of CD4+ T cells expressing CD25 and Foxp3, a transcription factor. Treg cells maintain immunological self-tolerance in mice and humans, and suppress autoimmunity and other various immune responses such as tumor immunity, transplant rejection, allergy, responses to microbes, and inflammation. Treg cell proliferation is controlled by antigen-presenting DCs. On the other hand, Treg cells suppress the function of DCs by restraining DC maturation. Therefore, the interaction between DCs and Treg cells, DC-Treg crosstalk, could contribute to controlling health and disease. We recently found that unique DC-Treg crosstalk plays a role in several conditions. First, Treg cells are expanded in ultraviolet-B (UVB)-exposed skin by interacting with DCs, and the UVB-expanded Treg cells have a healing function. Second, manipulating DC-Treg crosstalk can induce effective acquired immune responses against SARS-CoV2 antigens without adjuvants. Third, Treg cells with a special feature interact with DCs in the tumor microenvironment of human head and neck squamous cell cancer, which may contribute to the prognosis. Understanding the underlying mechanisms of DC-Treg crosstalk may provide a novel strategy to control health and disease.
PubMed: 38953561
DOI: 10.1093/intimm/dxae042 -
MBio Jul 2024an opportunistic fungal pathogen, produces the quorum-sensing molecule farnesol, which we have shown alters the transcriptional response and phenotype of human...
an opportunistic fungal pathogen, produces the quorum-sensing molecule farnesol, which we have shown alters the transcriptional response and phenotype of human monocyte-derived dendritic cells (DCs), including their cytokine secretion and ability to prime T cells. This is partially dependent on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ), which has numerous ligands, including the sphingolipid metabolite sphingosine 1-phosphate. Sphingolipids are a vital component of membranes that affect membrane protein arrangement and phagocytosis of by DCs. Thus, we quantified sphingolipid metabolites in monocytes differentiating into DCs by High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Farnesol increased the activity of serine palmitoyltransferase, leading to increased levels of 3-keto-dihydrosphingosine, dihydrosphingosine, and dihydrosphingosine 1-phosphate and inhibited dihydroceramide desaturase by inducing oxidative stress, leading to increased levels of dihydroceramide and dihydrosphingomyelin species and reduced ceramide levels. Accumulation of dihydroceramides can inhibit mitochondrial function; accordingly, farnesol reduced mitochondrial respiration. Dihydroceramide desaturase inhibition increases lipid droplet formation, which we observed in farnesol-treated cells, coupled with an increase in intracellular triacylglycerol species. Furthermore, inhibition of dihydroceramide desaturase with either farnesol or specific inhibitors impaired the ability of DCs to prime interferon-γ-producing T cells. The effect of farnesol on sphingolipid metabolism, triacylglycerol synthesis, and mitochondrial respiration was not dependent on PPAR-γ. In summary, our data reveal novel effects of farnesol on sphingolipid metabolism, neutral lipid synthesis, and mitochondrial function in DCs that affect their instruction of T cell cytokine secretion, indicating that can manipulate host cell metabolism via farnesol secretion.IMPORTANCE is a common commensal yeast, but it is also an opportunistic pathogen which is one of the leading causes of potentially lethal hospital-acquired infections. There is growing evidence that its overgrowth in the gut can influence diseases as diverse as alcohol-associated liver disease and COVID-19. Previously, we found that its quorum-sensing molecule, farnesol, alters the phenotype of dendritic cells differentiating from monocytes, impairing their ability to drive protective T cell responses. Here, we demonstrate that farnesol alters the metabolism of sphingolipids, important structural components of the membrane that also act as signaling molecules. In monocytes differentiating to dendritic cells, farnesol inhibited dihydroceramide desaturase, resulting in the accumulation of dihydroceramides and a reduction in ceramide levels. Farnesol impaired mitochondrial respiration, known to occur with an accumulation of dihydroceramides, and induced the accumulation of triacylglycerol and oil bodies. Inhibition of dihydroceramide desaturase resulted in the impaired ability of DCs to induce interferon-γ production by T cells. Thus, farnesol production by could manipulate the function of dendritic cells by altering the sphingolipidome.
PubMed: 38953353
DOI: 10.1128/mbio.00732-24 -
MBio Jul 2024Nasopharyngeal carriage of staphylococci spreads potentially pathogenic strains into (peri)oral regions and increases the chance of cross-infections. Some laboratory...
UNLABELLED
Nasopharyngeal carriage of staphylococci spreads potentially pathogenic strains into (peri)oral regions and increases the chance of cross-infections. Some laboratory strains can also move rapidly on hydrated agar surfaces, but the biological relevance of these observations is not clear. Using soft-agar [0.3% (wt/vol)] plate assays, we demonstrate the rapid surface dispersal of (peri)oral isolates of and and closely related laboratory strains in the presence of mucin glycoproteins. Mucin-induced dispersal was a stepwise process initiated by the passive spreading of the growing colonies followed by their rapid branching (dendrites) from the colony edge. Although most spreading strains used mucin as a growth substrate, dispersal was primarily dependent on the lubricating and hydrating properties of the mucins. Using JE2 as a genetically tractable representative, we demonstrate that mucin-induced dendritic dispersal, but not colony spreading, is facilitated by the secretion of surfactant-active phenol-soluble modulins (PSMs) in a process regulated by the quorum-sensing system. Furthermore, the dendritic dispersal of JE2 colonies was further stimulated in the presence of surfactant-active supernatants recovered from the most robust (peri)oral spreaders of and . These findings suggest complementary roles for lubricating mucins and staphylococcal PSMs in the active dispersal of potentially pathogenic strains from perioral to respiratory mucosae, where gel-forming, hydrating mucins abound. They also highlight the impact that interspecies interactions have on the co-dispersal of with other perioral bacteria, heightening the risk of polymicrobial infections and the severity of the clinical outcomes.
IMPORTANCE
Despite lacking classical motility machinery, nasopharyngeal staphylococci spread rapidly in (peri)oral and respiratory mucosa and cause cross-infections. We describe laboratory conditions for the reproducible study of staphylococcal dispersal on mucosa-like surfaces and the identification of two dispersal stages (colony spreading and dendritic expansion) stimulated by mucin glycoproteins. The mucin type mattered as dispersal required the surfactant activity and hydration provided by some mucin glycoproteins. While colony spreading was a passive mode of dispersal lubricated by the mucins, the more rapid and invasive form of dendritic expansion of and required additional lubrication by surfactant-active peptides (phenol-soluble modulins) secreted at high cell densities through quorum sensing. These results highlight a hitherto unknown role for gel-forming mucins in the dispersal of staphylococcal strains associated with cross-infections and point at perioral regions as overlooked sources of carriage and infection by staphylococci.
PubMed: 38953351
DOI: 10.1128/mbio.01562-24 -
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 -
IScience Jun 2024is an oral commensal bacterium that can colonize extraoral tumor entities, such as colorectal cancer and breast cancer. Recent studies revealed its ability to modulate...
is an oral commensal bacterium that can colonize extraoral tumor entities, such as colorectal cancer and breast cancer. Recent studies revealed its ability to modulate the immune response in the tumor microenvironment (TME), promoting cancer progression and metastasis. Importantly, subsp. was shown to bind to Siglec-7 via lipopolysaccharides, leading to a pro-inflammatory profile in human monocyte-derived dendritic cells. In this study, we show that subsp. RadD binds to Siglec-7 on NK cells, thereby inhibiting NK cell-mediated cancer cell killing. We demonstrate that this binding is dependent on arginine residue R124 in Siglec-7. Finally, we determine that this binding is independent of the known interaction of RadD with IgA. Taken together, our findings elucidate the targeting of Siglec-7 by subsp. RadD as a means to modulate the NK cell response and potentially promoting immune evasion and tumor progression.
PubMed: 38952680
DOI: 10.1016/j.isci.2024.110157 -
Heliyon Jun 2024Colon adenocarcinoma (COAD) is a serious public health issue due to high incidence and mortality rate. This study aimed to identify possible tumor antigens and...
BACKGROUND
Colon adenocarcinoma (COAD) is a serious public health issue due to high incidence and mortality rate. This study aimed to identify possible tumor antigens and necroptosis subtypes of COAD for the development of mRNA vaccines and the selection of appropriate patients for precision therapy.
METHODS
Gene expression profiles and clinical information for COAD were obtained from The Cancer Genome Atlas and Gene Expression Omnibus, respectively. We comprehensively studied the alterations in necroptosis-related genes (NRGs) using cBioPortal, and screened the hub NRGs associated with the prognosis of patients with COAD using Gene Expression Profiling Interactive Analysis 2. Consensuses clustering analysis was performed to identify necroptosis subtypes. Weighted gene co-expression network analysis (WGCNA) was used to identify the co-expression modules of the NRGs. The necroptosis landscape of COAD was assessed using graph learning-based dimensionality reduction. Finally, a drug sensitivity analysis of the two necroptosis subtypes was performed.
FINDINGS
Two tumor antigens, BLC-2-associated X protein (BAX) and interleukin 1 beta (IL1B) were identified based on their associations with prognosis of patients and antigen presenting cell infiltration. Two necroptosis subtypes (N1 and N2) were distinguished in patients with COAD, and they were characterized by their differential survival status and molecular expression levels of immune checkpoint proteins and immunogenetic cell death modulators. Furthermore, the necroptosis landscape of COAD indicated that individual patients had obvious heterogeneity. Co-expression modules were identified using WGCNA, and the hub NRGs were found to be involved in various immune processes. Drug sensitivity analysis indicated that there were significant differences in drug sensitivity between the N1 and N2 subtypes. Cell experiments suggested that both overexpression of BAX and IL1B promoted necroptosis of COAD cells and enhanced the cytotoxicity of CD8 T cells.
INTERPRETATION
BAX and IL1B are potential antigens for the development of anti-COAD mRNA vaccines, specifically for patients with the N2 subtype. Consequently, this study will guide the development of more effective immunotherapeutic approaches and the identification of appropriate patients.
PubMed: 38952359
DOI: 10.1016/j.heliyon.2024.e32531 -
ACS Nano Jul 2024Immunotherapy can potentially suppress the highly aggressive glioblastoma (GBM) by promoting T lymphocyte infiltration. Nevertheless, the immune privilege phenomenon,...
Immunotherapy can potentially suppress the highly aggressive glioblastoma (GBM) by promoting T lymphocyte infiltration. Nevertheless, the immune privilege phenomenon, coupled with the generally low immunogenicity of vaccines, frequently hampers the presence of lymphocytes within brain tumors, particularly in brain tumors. In this study, the membrane-disrupted polymer-wrapped CuS nanoflakes that can penetrate delivery to deep brain tumors via releasing the cell-cell interactions, facilitating the near-infrared II (NIR II) photothermal therapy, and detaining dendritic cells for a self-cascading immunotherapy are developed. By convection-enhanced delivery, membrane-disrupted amphiphilic polymer micelles (poly(methoxypoly(ethylene glycol)-benzoic imine-octadecane, mPEG--C18) with CuS nanoflakes enhances tumor permeability and resides in deep brain tumors. Under low-power NIR II irradiation (0.8 W/cm), the intense heat generated by well-distributed CuS nanoflakes actuates the thermolytic efficacy, facilitating cell apoptosis and the subsequent antigen release. Then, the positively charged polymer after hydrolysis of the benzoic-imine bond serves as an antigen depot, detaining autologous tumor-associated antigens and presenting them to dendritic cells, ensuring sustained immune stimulation. This self-cascading penetrative immunotherapy amplifies the immune response to postoperative brain tumors but also enhances survival outcomes through effective brain immunotherapy.
PubMed: 38952208
DOI: 10.1021/acsnano.4c06183 -
ACS Nano Jul 2024Chemo-immunotherapy has become a promising strategy for cancer treatment. However, the inability of the drugs to penetrate deeply into the tumor and form potent tumor...
Chemo-immunotherapy has become a promising strategy for cancer treatment. However, the inability of the drugs to penetrate deeply into the tumor and form potent tumor vaccines in vivo severely restricts the antitumor effect of chemo-immunotherapy. In this work, an injectable sodium alginate platform is reported to promote penetration of the chemotherapeutic doxorubicin (DOX) and delivery of personalized tumor vaccines. The injectable multifunctional sodium alginate platform cross-links rapidly in the presence of physiological concentrations of Ca, forming a hydrogel that acts as a drug depot and releases loaded hyaluronidase (HAase), DOX, and micelles (IP-NPs) slowly and sustainedly. By degrading hyaluronic acid (HA) overexpressed in tumor tissue, HAase can make tumor tissue "loose" and favor other components to penetrate deeply. DOX induces potent immunogenic cell death (ICD) and produces tumor-associated antigens (TAAs), which could be effectively captured by polyethylenimine (PEI) coated IP-NPs micelles and form personalized tumor vaccines. The vaccines efficaciously facilitate the maturation of dendritic cells (DCs) and activation of T lymphocytes, thus producing long-term immune memory. Imiquimod (IMQ) loaded in the core could further activate the immune system and trigger a more robust antitumor immune effect. Hence, the research proposes a multifunctional drug delivery platform for the effective treatment of colorectal cancer.
PubMed: 38952130
DOI: 10.1021/acsnano.4c04766 -
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi =... Jun 2024Macrophage migration inhibitor factor (MIF), as a pro-inflammatory and oncogenic cytokine, is highly expressed in a variety of malignant tumors and recruits tumor cells... (Review)
Review
Macrophage migration inhibitor factor (MIF), as a pro-inflammatory and oncogenic cytokine, is highly expressed in a variety of malignant tumors and recruits tumor cells or immune cells into the tumor microenvironment. MIF affects the development of tumor by altering the tumor microenvironment. In the process of tumor, MIF not only plays an anti-inflammatory role, but also promotes tumorigenesis by immune escape and immune tolerance.This is closely related to immune cells that play a role in the tumor immune response, mainly including natural killer (NK) cells, macrophages, dendritic cells, B cells, T cells and myeloid-derived suppressor cells. The article summarizes the role of MIF in tumor immune and the relationship between MIF and the development of malignant tumors, in order to provide new ideas and possible therapy for tumor treatment.
Topics: Macrophage Migration-Inhibitory Factors; Humans; Neoplasms; Animals; Tumor Microenvironment; Killer Cells, Natural; Macrophages; Dendritic Cells; T-Lymphocytes
PubMed: 38952097
DOI: No ID Found