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PubMed2026

Exploring Endoplasmic Reticulum Stress-Related Genes in Cartilage Defects: Implications for Diagnosis and Therapy.

INTRODUCTION: Cartilage defects (CDs) are orthopedic conditions with limited regenerative potential. This study aimed to identify endoplasmic reticulum (ER) stress-related biomarkers and construct a diagnostic model to enhance the early detection of CD. METHODS: This study analyzed the transcriptomic dataset GSE129147 to identify ER stressrelated differentially expressed genes (ERSRDEGs) between CD and control tissues using the limma package (version 3.58.1). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were employed for functional enrichment. Immune infiltration was assessed using cell-type identification, which involved estimating the relative subsets of RNA transcripts and single-sample gene set enrichment analysis. Diagnostic models were constructed using logistic regression, support vector machine, and least absolute shrinkage and selection operator regression. RESULTS: Twenty ERSRDEGs were identified, with CYBB, ATP6V1A, and TNFRSF12A significantly upregulated in CD samples. GO and KEGG analyses highlighted oxidative stress response and extracellular matrix remodeling as key mechanisms in CD pathogenesis. Immune analysis revealed an increase in regulatory T cells and a reduction in CD8. T cells. TNFRSF12A showed strong immune associations and, together with TWIST1 and ATP6V1A, formed the final preliminary diagnostic model. The preliminary LASSO model achieved satisfactory predictive accuracy (AUC: 0.7-0.9). DISCUSSION: These findings suggest that ER stress and immune imbalance jointly contribute to cartilage degeneration. The identified genes, particularly TNFRSF12A, TWIST1, and ATP6V1A, not only serve as potential biomarkers but also provide preliminary evidence for new mechanistic insights into stress-immune crosstalk in CD. CONCLUSION: This study reveals the key roles of ER stress and immune dysregulation in CDs. Moreover, the ERSRDEG-based diagnostic model provides preliminary bioinformatics evidence and potential molecular indicators for targeted diagnostics and therapies.

Humans↗

PubMed2007

Efficacy of an osmotic pump delivered, GM-CSF-based tumor vaccine in the treatment of upper aerodigestive squamous cell carcinoma in rats.

PURPOSE: Upper aerodigestive tract (UADT) cancer has not experienced significant overall survival improvement for over 20 years, and no successful treatments for systemic disease exist. Most patients with UADT cancer experience immune suppression, therefore immune restorative therapies may offer promise for these patients. We presently tested the efficacy of granulocyte macrophage-colony stimulating factor (GM-CSF) delivered via 28-day continuous infusion pump, in combination with irradiated tumor cells, in a flank model of UADT cancer. METHODS: Five groups of rats were inoculated with syngeneic mucosally derived squamous carcinoma cells (FAT-7). Osmotic minipumps were implanted in the contralateral flank to deliver GM-CSF at 0 (PBS), 0.1, 1, 10, or 100 ng/day (n = 6 per group) for 28 days; 10(6) irradiated FAT-7 cells (ITC) were injected at the site of the GM-CSF infusion on days 0, 3, 7, 14, and 21 immune infiltrates in tumors were analyzed. RESULTS: Rats that received 10 or 100 ng/day GM-CSF/ITC had a significantly slower tumor growth rate compared to those who received 0, 0.1, or 1 ng/day (ANOVA, P < 0.01). There were increased CD 4+, CD 8+, and CD 68+ cells in tumors of GM-CSF/ITC treated animals over controls. CONCLUSION: GM-CSF (10 or 100 ng/day) delivered locally via osmotic pump with ITC slows the growth rate of mucosally derived squamous cell carcinoma in rats while improving immune cell infiltrates. The efficacy of locally delivered GM-CSF immunotherapy in this model may be a first step toward this immunotherapy strategy for humans.

Animals↗

PubMed2025

Long non-coding RNA NEAT1 promotes colorectal cancer progression via interacting with SIRT1.

Nuclear-enriched abundant transcript 1 (NEAT1), a long noncoding RNA, is found to be significantly dysregulated in different types of cancer, including colorectal cancer (CRC). Nevertheless, there is still much to learn about the precise functions and processes of NEAT1 in the progression of CRC. Using The Cancer Genome Atlas (TCGA) database and 50 CRC specimens from the First Affiliated Hospital of Dali University, we assessed the expression of NEAT1 to determine its clinical impact. Through gene set enrichment analysis (GSEA), Cancer Single-cell State Atlas (CancerSEA), and immune infiltration studies, we elucidated key functions of NEAT1. We utilized Cell Counting Kit-8 (CCK8), wound healing, and Transwell assays to investigate the role of NEAT1 in the progression of CRC. Through the use of GSEA and immunohistochemistry, additional investigations were conducted to unveil the downstream targets of NEAT1 and gain insights into their regulatory dynamics. Our in vitro studies confirmed the regulatory role of NEAT1 in CRC. Findings indicate that increased NEAT1 expression correlates with adverse outcomes in colorectal tissues. In the CRC model, reduced levels of NEAT1 lead to reduced cell proliferation, invasion, and migration. Additionally, NEAT1 influenced immune cell infiltration in CRC and functioned as an oncogene by upregulating Sirtuin 1 (SIRT1) expression. This study demonstrates that NEAT1 promotes CRC progression and metastasis through a SIRT1-mediated mechanism, suggesting its potential as a prognostic biomarker and therapeutic target for CRC.

RNA, Long Noncoding↗

PubMed2026

Hypoxia-inducible factor-1α promotes the malignant progression of cervical cancer cells by regulating lactate dehydrogenase A-mediated glycolysis.

BACKGROUND: Enhanced glycolysis is a hallmark of metabolic reprogramming in cervical cancer and plays a key role in tumor progression. Hypoxia-inducible factor-1α (HIF-1α), a core regulator of glycolytic metabolism, remains incompletely characterized in cervical cancer. This study aimed to investigate the expression pattern and clinical significance of HIF-1α in cervical cancer, and to explore its association with malignant biological behavior and lactate dehydrogenase A (LDHA)-related glycolytic metabolism in cervical cancer cells. METHODS: The expression level, clinicopathological features, immune infiltration correlation, and prognostic value of HIF-1α in cervical cancer were analyzed based on the The Cancer Genome Atlas (TCGA) database. HIF-1α overexpression and knockdown models were established in HeLa and Caski cells. Cell viability and invasive ability were assessed by Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to detect changes in LDHA expression. Lactate production was measured using a lactate assay kit, and intracellular reactive oxygen species (ROS) levels were determined by flow cytometry. RESULTS: Bioinformatics analysis showed that HIF-1α was highly expressed in cervical cancer and was closely associated with patient age, menopausal status, immune cell infiltration, and poor prognosis. Kaplan-Meier survival analysis demonstrated that patients with high HIF-1α expression had significantly worse overall survival (OS) than those with low expression. In vitro functional experiments further confirmed that HIF-1α overexpression significantly enhanced the viability and invasive ability of HeLa and Caski cells, whereas HIF-1α knockdown produced the opposite effects. HIF-1α overexpression was associated with increased messenger RNA (mRNA) and protein expression levels of LDHA, a key glycolytic molecule, along with increased lactate production and elevated intracellular ROS levels. CONCLUSIONS: HIF-1α is aberrantly highly expressed in cervical cancer and may enhance glycolytic activity by upregulating LDHA expression, thereby promoting the proliferation and invasion of cervical cancer cells. These findings suggest that HIF-1α could serve as a potential diagnostic, prognostic, and therapeutic target biomarker for cervical cancer.

Hypoxia-inducible factor-1α (HIF-1α)↗

PubMed2025

Expression and prognosis of CXCL13 in uterine corpus endometrial carcinoma based on bioinformatics analysis.

OBJECTIVE: The biological significance of the chemokine ligand C-X-C motif chemokine ligand 13 (CXCL13) may play a significant role in the pathogenesis of uterine corpus endometrial carcinoma (UCEC). This study aims to identify and verify CXCL13 with predictive value for prognosis in UCEC. METHODS: CXCL13 mRNA expression differences were analyzed using R software in three independent datasets: one each from The Cancer Genome Atlas (TCGA) and two from the Gene Expression Omnibus (GEO), namely GSE17025 and GSE106191. The correlation between CXCL13 expression and prognosis was evaluated by Kaplan-Meier analysis. Univariate and multivariate Cox analyses were utilized to construct a prognostic nomogram. Tumor Immune Estimation Resource (TIMER) and the Tumor and Immune System Interaction Database (TISIDB) were employed to assess the relationship between CXCL13 and tumor immune infiltration. Coexpressed genes with CXCL13 were identified by the Spearman correlation analysis. A CXCL13 protein-protein interaction (PPI) network was constructed with the STRING website tool and hub genes were screened out. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analyses were performed with the "clusterProfiler" R package. Gene set enrichment analysis (GSEA) was used to identify underlying biological mechanisms. A drug-gene interaction network was constructed in the Comparative Toxicogenomics Database (CTD). RESULTS: High CXCL13 mRNA expression were validated in UCEC in the above three independent datasets. High CXCL13 expression was associated with favorable prognosis in UCEC. A nomogram for predicting the 1-, 3-, and 5-year survival probability in UCEC was construct based on CXCL13 expression and other clinical parameters. The use of Spearman correlation indicated certain correlation between CXCL13 and immune cells and immune checkpoint (ICP) genes. Seven hub genes were upregulated in UCEC, namely CXCL9, IFNG, CXCL10, CXCL11, GBP5, CCL18, and GZMB. The expression and prognostic relevance of CXCL9, IFNG, GBP5, and GZMB were in accordance with CXCL13. The main biological processes enriched were cytokine-cytokine receptor interaction and chemokine signaling pathway. CONCLUSIONS: The above comprehensive analyses suggest that CXCL13 may serve as a potential prognostic biomarker for UCEC, specifically for early-stage UCEC.

CXCL13↗

PubMed2025

Oncogenic EME1 promotes tumor progression and immune modulation in human cancers with therapeutic targeting potential.

BACKGROUND: EME1, a critical DNA repair endonuclease, has emerged as a potential oncogene implicated in genome instability and cancer progression. However, its pan-cancer roles, prognostic significance, immune interactions, and therapeutic targeting remain underexplored. METHODS: We conducted a comprehensive pan-cancer analysis integrating multi-omics data from public databases, including TIMER2.0, GEPIA2, TISIDB, and cBioPortal, to evaluate EME1 expression, genetic alterations, and their association with clinical outcomes, immune infiltration, and molecular pathways. Virtual screening of 3180 FDA-approved drugs and molecular dynamics (MD) simulations were employed to identify and validate potential EME1 inhibitors. RESULTS: EME1 was significantly overexpressed in various human cancers and positively associated with advanced tumor grade and stage. High EME1 expression and mutations were linked to poor overall and disease-free survival. Immunogenomic profiling revealed strong positive correlations between EME1 and myeloid-derived suppressor cells (MDSCs), alongside a negative association with endothelial cell function, suggesting immunosuppressive roles. Machine learning models based on EME1-associated genes demonstrated high predictive accuracy for liver hepatocellular carcinoma (AUC > 0.90). Virtual screening identified eight promising drug candidates, including Everolimus and Dioscin, with strong binding affinities. MD simulations confirmed the stability of these interactions, particularly for Dioscin. CONCLUSION: This study reveals the multifaceted oncogenic roles of EME1 in tumor progression, immune evasion, and prognosis. It proposes EME1 as a promising biomarker and therapeutic target across multiple cancer types. The identified drug candidates warrant further in vitro and in vivo validation for potential repurposing in EME1-targeted cancer therapy.

EME1↗

PubMed2026

Unveiling the power of TIIC: A prognostic tool for esophageal adenocarcinoma.

BACKGROUND: Esophageal adenocarcinoma (EAC) remains a lethal malignancy with limited prognostic tools for guiding immunotherapy. Tumor-infiltrating immune cells (TIICs) play a critical role in EAC prognosis and treatment response. METHODS: We integrated single-cell RNA sequencing and bulk transcriptome data from TCGA and GEO databases. TIIC-specific RNAs were identified via tissue specificity index calculation combined with machine learning feature selection. Twenty machine learning algorithms were benchmarked to construct an optimal TIIC signature score (TIIC-Score) based on the comprehensive C-index. Immunotherapy response, genomic mutation, and copy number variation were analyzed. Summary-data-based Mendelian randomization (SMR) and two-sample Mendelian randomization (MR) were performed to explore genetic associations. Core prognostic TIIC-related genes were functionally validated in esophageal cancer cell lines through loss-of-function assays. RESULTS: The TIIC-Score demonstrated robust prognostic value for 1-, 2-, and 3-year overall survival across multiple cohorts, outperforming 22 published models. High TIIC-Score was associated with poor survival and increased chromosomal instability. Mutation profiling revealed high frequencies of TP53 (78.2%), TTN (48.7%), and SYNE1 (30.8%). MR analysis identified a significant association between gastro-oesophageal reflux and EAC risk at SNP rs8130507. Functionally, CCNI was upregulated in esophageal cancer cells, and its knockdown suppressed malignant phenotypes while promoting apoptosis, supporting its pro-tumorigenic role. CONCLUSION: The TIIC-Score provides a novel prognostic framework for EAC that effectively stratifies patient risk and may help identify individuals most likely to benefit from immunotherapy.

Esophageal adenocarcinoma↗

PubMed2025

Tumor Signatures of Physical Fitness: Insights from a Preclinical Model.

PURPOSE: Cardiorespiratory fitness (CRF) and muscle strength are associated with cancer risk/mortality in adults. However, there is yet no evidence for pediatric tumors. This study investigated the association of CRF and muscle strength with several tumor-related phenotypes in an aggressive childhood malignancy, high-risk neuroblastoma. METHODS: Twelve mice-bearing orthotopic high-risk neuroblastomas were studied. CRF and muscle strength were assessed using treadmill and grip strength testing, respectively. The following tumor-related outcomes were studied: survival, clinical severity, tumor weight/volume, metastasis, and intratumor immune infiltrates. In addition, tumor samples underwent quantitative proteomic analysis via liquid chromatography-tandem mass spectrometry. Spearman correlations (or logistic regression) were performed between CRF/muscle strength and the abovementioned variables. Proteins that were significantly correlated with CRF or muscle strength were mapped into protein-protein interaction (PPI) networks using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. RESULTS: CRF was inversely correlated with clinical severity score ( r = -0.657, P = 0.020). Of 6840 identified tumor proteins, 76 correlated significantly with CRF (19 positively, 57 negatively), whereas 194 correlated with muscle strength (97 positively, 97 negatively). Proteins correlated with CRF were primarily involved in metabolic and structural pathways, including angiotensinogen and elastin. In turn, muscle strength-associated proteins were more abundant and included keratin family proteins (e.g., keratin, type I cytoskeletal 14, and type II cytoskeletal 5), proteins involved in cell adhesion (e.g., desmoglein-1-alpha), and translational regulators (e.g., eukaryotic initiation factor 4A). Network analysis revealed significant enrichment in structural organization and cellular adhesion pathways. CONCLUSIONS: Besides the association of CRF with clinical severity of the tumor, distinct novel tumor proteomic signatures associated with CRF and muscle strength were identified, highlighting potential mechanisms linking physical fitness with childhood cancer biology.

Muscle Strength↗

PubMed2026

KLHL17 as a Prognostic Indicator and Therapeutic Target in Cervical Cancer: A Comprehensive Analysis.

INTRODUCTION: This study aims to clarify the role of kelch like family member 17 (KLHL17) in cervical cancer (CESC) is unclear. OBJECTIVE: To clarify this uncertainty, our research employed bioinformatics analysis coupled with experimental corroboration. METHODS: We utilized the Cancer Genome Atlas (TCGA) database to assess the expression of KLHL17 in various cancers, specifically CESC, and to explore its association with clinical characteristics, diagnostic utility, and prognostic significance in CESC. The current investigation delved into the potential regulatory pathways related to KLHL17, examining its connection with the infiltration of immune cells, the expression of immune checkpoint genes, the status of microsatellite instability (MSI), and the efficacy of diverse therapeutic agents in CESC. The research analyzed KLHL17 expression patterns using single-cell sequencing data from CESC samples and investigated the genetic variations of KLHL17 within this context. KLHL17 expression was validated using GSE145372. The presence and levels of KLHL17 in different cell lines were validated through quantitative real-time PCR (qRT-PCR) assays. RESULTS: KLHL17 exhibited irregular expression profiles across various cancer types, including CESC. Furthermore, increased KLHL17 levels in CESC patients were significantly associated with a lower progression-free survival (PFS) rate (hazard ratio: 1.62; 95% confidence interval: 1.01-2.60, p = 0.044). Moreover, KLHL17 expression emerged as a distinct prognostic indicator for CESC patients (p = 0.031). It has been associated with various biological pathways, such as cytokine-cytokine receptor interaction, primary immunodeficiency, cell adhesion molecules (CAMs), chemokine signaling pathway, steroid hormone biosynthesis, and others. The expression levels of KLHL17 were found to correlate with the presence of immune cells, the expression of immune checkpoint genes, and the status of MSI within CESC. Furthermore, KLHL17 expression exhibited a significant and inverse correlation with XMD15-27, rTRAIL, Paclitaxel, tp4ek, and tp4ek-k6. Furthermore, KLHL17 was found to be significantly positively regulated in CESC cell lines. DISCUSSION: The findings suggest that KLHL17 is involved in the progression of CESC and may serve as a potential prognostic marker and therapeutic target. KLHL17's association with immune cell infiltration and immune checkpoint genes indicates a role in immuneevasion. Future research should focus on validating these findings through independent datasets and experimental studies to elucidate the molecular mechanisms underlying KLHL17's role in CESC progression and immune regulation. CONCLUSION: KLHL17 is a promising prognostic marker and potential therapeutic target in CESC.

Humans↗

PubMed1991

Effect of immunosuppression on rejection of cartilage formed by transplanted allogeneic rib chondrocytes in mice.

The effect of short-term immunosuppressive treatment with antithymocyte serum-procarbazine (ATS-PCH) and cyclosporin-A (Cy-A) on survival of allogeneic rib chondrocyte grafts was examined morphologically and by evaluation of specific humoral and cellular antigraft immunity. The latter were evaluated by means of leukoagglutination and the indirect migration inhibition assay, respectively. Untreated recipients of syngeneic rib chondrocytes and untreated recipients of whole syngeneic and allogeneic rib cartilage served as controls. Transplanted syngenic rib chondrocytes formed cartilaginous nodules similar to rib cartilage in situ. These nodules contained hypertrophied chondrocytes, but neither physiologic resorption by vascularized connective tissue nor bone formation occurred after an observation period of longer than six weeks. Transplantation of allogeneic chondrocytes resulted in development of humoral and cellular antigraft immunity, and the formed cartilage was destroyed by infiltrating immune cells. Immunosuppression by ATS-PCH resulted in inhibition of graft destruction and a marked decrease of specific humoral antigraft immunity. Cellular antigraft immunity did not occur. Moreover, neither the histologic appearance of the cartilaginous nodules nor the results of immunologic response evaluations in the ATS-PCH-treated group differed from those in untreated whole allogeneic cartilage recipients. Treatment with Cy-A did not significantly improve survival cartilage formed by allogeneic chondrocytes.

Animals↗

PubMed2026

Loss of tumor-infiltrating lymphocytes and poor response to immunotherapy in IDH GOF mutant melanoma.

Recent innovations in melanoma treatment with immune checkpoint blockade (ICB) have improved overall outcomes for patients; however, over 50% of patients still develop resistance to treatment. These patients either have intrinsic resistance and never respond to therapy or develop acquired resistance months or years into treatment. The mechanisms underlying ICB resistance remain poorly understood. Our data show that patients with isocitrate dehydrogenase gain-of-function (IDH GOF) mutant melanoma have a worse response to anti-PD1 immunotherapy. IDH mutations have been found to be oncogenic and associated with differential methylation in multiple cancers but are not yet characterized in human melanoma. Here, we investigate the clinical, immune, and transcriptional phenotypes of IDH GOF melanomas through analyses of clinical response, single-cell RNA-seq, bulk RNA-seq, and DNA methylation data. Single-cell data analysis showed decreased immune infiltrate and activity in the IDH GOF tumors. Bulk sequencing data demonstrated the association among IDH mutation, immune exclusion, and disruptions in global DNA methylation. The melanoma-derived genomic data presented support previously described resistance mechanisms of IDH mutation in other cancer types and is the first demonstration to our knowledge of the role of IDH GOF in the human melanoma tumor microenvironment.

Humans↗

PubMed2006

CD4+CXCR4highCD69+ T cells accumulate in lung adenocarcinoma.

The chemokine receptor CXCR4 is involved in the growth and metastasis of tumor cells. However, the expression of its ligand, the chemokine CXCL12, in tumors and its role in regulating the accumulation of immune cells within the tumors is not clear. Using ELISA and immunohistochemistry we found that CXCL12 is expressed in the majority of nonsmall cell lung cancer tissue sections obtained from stage IA to IIB nonsmall cell lung cancer patients undergoing operation. Histopathologic examination of these sections indicated that high CXCL12 expression correlated with increased tumor inflammation. In addition, disease recurrence rates in a subgroup of adenocarcinoma patients showed a tendency to correlate with high CXCL12 expression in the tumor. Isolation of adenocarcinoma-infiltrating immune cells demonstrated an increase in the percentage of CD4+CD69+CXCR4+ T cells as compared with normal lung tissue. About 30% of these cells expressed the regulatory T cell markers CD25high and FoxP3. The percentage of CD8 T cells within the tumor did not change, however; the percentage of NK and NK T cells was significantly reduced. In correlation with CXCR4 expression, CD4 T cells showed increased migration in response to CXCL12 compared with CD8 T cells and NK cells. Overall, these observations suggest that CXCL12 expression may influence tumor progression by shaping the immune cell population infiltrating lung adenocarcinoma tumors.

Adenocarcinoma↗

PubMed1995

Clinical evidence that the human monoclonal anti-idiotypic antibody 105AD7, delays tumor growth by stimulating anti-tumor T-cell responses.

A human monoclonal anti-idiotypic antibody, 105AD7, which mimics a colorectal tumor associated antigen, 791Tgp72, has been developed. A Phase I trial in advanced colorectal cancer patients showed that 105AD7 therapy was nontoxic and that immunised patients had prolonged survival when compared to a contemporary group of patients treated in the same center. There is accumulating clinical evidence that 105AD7 delays tumor growth by stimulating anti-tumor T-cell responses. Stimulation of helper T-cells was exemplified in the phase I study as 105AD7 immunized patients showed antigen specific T-cell blastogenesis responses and enhanced IL-2 production. Further evidence was obtained from a new clinical study in which colorectal cancer patients were immunized prior to tumor resection. Immune infiltrating cells were analysed by immunohistochemistry and effector cell function was studied in immune cells from peripheral blood and tumor draining lymph nodes. Both activated CD4 and natural killer (NK) cells were observed at the tumor site, which is of interest as NK cells are rarely found in colorectal tumors. Effector studies confirmed that NK activity was enhanced in 3/6 patients. Increased autologous tumor killing was also found in 3/4 patients and accumulation of CD8RO cells following 105AD7 immunization also suggested that CD8 T cells were being stimulated.

Aged↗

PubMed2006

Regulatory T cells and innate immune regulation in tumor immunity.

Innate and adaptive immunity play important roles in immunosurveillance and tumor destruction. However, increasing evidence suggests that tumor-infiltrating immune cells may have a dual function: inhibiting or promoting tumor growth and progression. Although regulatory T (Treg) cells induce immune tolerance by suppressing host immune responses against self- or nonself-antigens, thus playing critical roles in preventing autoimmune diseases, they might inhibit antitumor immunity and promote tumor growth. Recent studies demonstrate that elevated proportions of Treg cells are present in various types of cancers and suppress antitumor immunity. Furthermore, tumor-specific Treg cells can inhibit immune responses only when they are exposed to antigens presented by tumor cells. Therefore, Treg cells at tumor sites have detrimental effects on immunotherapy directed to cancer. This review will discuss recent progress in innate immunity, Treg cells, and their regulation through Toll-like receptor (TLR) signaling. It was generally thought that TLR-mediated recognition of specific structures of invading pathogens initiate innate and adaptive immune responses through dendritic cells. New evidence suggests that TLR signaling may directly regulate the suppressive function of Treg cells. Linking TLR signaling to the functional control of Treg cells opens intriguing opportunities to manipulate TLR signaling to control both innate and adaptive immunity against cancer.

Animals↗

PubMed1996

Surgical implications of tumour immunology.

The presence of immune infiltration of tumour deposits and the existence of effective in vitro anti-tumour immune responses would suggest the possibility of therapeutic manipulation against tumour cells. However, clinical immunotherapy has shown little promise as a cancer treatment. Numerous explanations for this inefficacy have been proposed, one of which involves the elaboration of immunosuppressive moieties from tumour cells. The results of studies presented below show that serum from patients with gastrointestinal and other tumours have immunosuppressive influences on normal lymphocytes. The degree of this in vitro inhibition is related to tumour 'bulk' and may reflect a systemic immunosuppressive influence of the tumour. Isolation and culture of lymphocytes from gastrointestinal tumour deposits demonstrated that these immune cells are functionally inert, suggesting the existence of an immunosuppressive tumour microenvironment. The isolation and partial purification of an immunosuppressive moiety from conditioned culture medium of a variety of human tumour cell lines further supports the hypothesis of tumour-mediated immunosuppression. A number of protein tumour cell products have been described with potent immunosuppressive properties. These include transforming growth factor-beta, interleukin-10, and the retroviral envelope protein p15E. The surgical implications of the proposed tumour-host immune relationship includes the hypothesis that clinically apparent disease may not be amenable to immune attack owing to tumour-mediated immune suppression. The use of immunostimulatory strategies as adjuvant perioperative therapy would seem a more effective environment for the activation of antitumour immune responses in the surgical patient.

Combined Modality Therapy↗

PubMed1999

Costimulatory markers in muscle of patients with idiopathic inflammatory myopathies and in cultured muscle cells.

In an attempt to understand the mechanisms of cell injury in the inflammatory myopathies, we analyzed the expression of costimulatory molecules, CTLA4, CD28, CD86, CD40, and CD154 as well as HLA class I, HLA class II, and ICAM-I in normal muscle and in muscle biopsies from patients with polymyositis (PM) or dermatomyositis (DM). By immunohistochemical staining, DM and PM biopsies showed the presence of CTLA4, CD28, CD86, and CD40 on inflammatory cells. More strikingly, however, low levels of CTLA4 and CD28 were observed on muscle cells. The expression of CTLA4 and CD28 on nonlymphoid cells has not been previously reported. These unexpected findings were confirmed in cultured normal human myoblasts: various proinflammatory cytokines induced the expression of CTLA4 and CD28 on normal human muscle cells. The sequences of the cDNAs were found to be identical to the sequences for these molecules in T cells. The data suggest a novel complexity in the network of cellular interactions between the infiltrated immune cells and the muscle cells in which the normal relationship between infiltrating inflammatory cells and target tissue is under a previously unrecognized set of controls.

Abatacept↗

PubMed1999

Ectopic expression of the nude gene induces hyperproliferation and defects in differentiation: implications for the self-renewal of cutaneous epithelia.

Nude mice are characterized by the absence of visible hair, epidermal defects, and the failure to develop a thymus. This phenotype results from loss-of-function mutations in Whn (Hfh11), a winged-helix transcription factor. In murine epidermis and hair follicles, endogenous whn expression is induced as epithelial cells initiate terminal differentiation. Using the promoter for the differentiation marker involucrin, transgenic mice that ectopically express whn in stratified squamous epithelia, hair follicles, and the transitional epithelium of the urinary tract were generated. Transgenic epidermis and hair follicles displayed impaired terminal differentiation and a subset of hair defects, such as delayed growth, a waved coat, and curly whiskers, correlated with decreased transforming growth factor (TGF)-alpha expression. The exogenous Whn protein also stimulated epithelial cell multiplication. In the epidermis, basal keratinocytes exhibited hyperproliferation, though transgene expression was restricted to suprabasal, postmitotic cells. Hair follicles failed to enter telogen (a resting period) and remained continuously in an abnormal anagen (the growth phase of the hair cycle). Ureter epithelium developed severe hyperplasia, leading to the obstruction of urine outflow and death from hydronephrosis. Though an immune infiltrate was present occasionally in transgenic skin, the infiltrate was not the primary cause of the epithelial hyperproliferation, as the immune reaction was not observed in all affected transgenics, and the transgene induced identical skin and urinary tract abnormalities in immunodeficient Rag1-null mice. Given the effects of the transgene on cell proliferation and TGFalpha expression, the results suggest that Whn modulates growth factor production by differentiating epithelial cells, thereby regulating the balance between proliferative and postmitotic populations in self-renewing epithelia.

Animals↗

PubMed2026

Immune subtyping of colorectal adenoma identifies a subtype with activated adaptive immunity ahead of progressing to cancer.

BACKGROUND: Colorectal adenomas (CRA) represent precursor lesions with varying risks of malignant transformation. However, molecular subtyping, particularly immune-related classification, remains underexplored in adenomas. This study aims to characterize the immune landscape of CRA through immune subtyping and evaluate its association with cancer progression, gene expression signatures, and functional pathways. METHODS: We conducted a retrospective analysis of transcriptomic data from multiple cohorts of CRA samples. Immune subtypes were identified using non-negative matrix factorization (NMF) based on immune-related genes. Diverse deconvolution algorithms were used to estimate immune cell infiltration. The immune status alteration in premalignant lesion was further consolidated by single-cell transcriptome data. Differential gene expression analysis was performed between subtypes, followed by functional enrichment analyses (Gene Ontology [GO] and Kyoto Encyclopedia of Genes and Genomes [KEGG]). RESULTS: Two distinct immune subtypes were identified: an immune-enriched subtype characterized by high lymphocyte infiltration and elevated expression of immune-related genes, and an immune-deficient subtype with suppressed immune activity. Differential expression analysis revealed significant upregulation of immune response genes (e.g., CD4, CD86, HLA-DRA) in the immune-enriched subtype. GO and KEGG analyses highlighted enrichments in leukocyte transendothelial migration, chemokine signaling, and antigen processing and presentation pathways. Single-cell result revealed an early occurrence of TIGIT activation and exhausted CD8 T cell features in adenoma when compared to normal tissue. CONCLUSION: This study delineates distinct immune subtypes within CRAs. The immune-enriched subtype demonstrates activated adaptive immunity and may reflect a higher potential for immune surveillance, while the immune-deficient subtype exhibits stromal features suggestive of progressive transformation. These findings provide insights into early immune microenvironment alterations and may inform strategies for risk stratification and immunoprevention in colorectal carcinogenesis.

Colorectal adenoma↗