Tumor-promoting Activity Research Articles

Study on association between human plasma polybrominated diphenyl ethers (PBDEs) and thyroid homeostasis and carcinoma.

Polybrominated diphenyl ethers (PBDEs), a category of persistent organic pollutants (POPs), are ubiquitous in the environment and have been reported to have endocrine-disrupting and tumor-promoting activities. However, the evidence for the correlation between plasma PBDEs levels, thyroid homeostasis and thyroid carcinoma in humans remains limited. Herein, we analyzed eight PBDE congeners in 53 patients undergoing thyroid surgery. BDE-209 was identified as the most abundant PBDE congener in plasma (median, 11.36ng/g lipid). BDE-100 concentration was positively associated with free triiodothyronine (FT3), indicating a potential interference with thyroid function. Point-biserial correlation analysis revealed positive associations between certain plasma PBDE congeners (BDE-28, BDE-47, BDE-99, BDE-100, and BDE-154) and aggressive pathological parameters. There was no significant correlation between PBDEs and BRAF or RAS mutations in PTC patients, indicating that PBDEs may not directly promote the initiation and progression of thyroid cancer through these genetic mutations. It implies the complexity of the relationship between PBDEs exposure and thyroid cancer development. Although not statistically significant, Bayesian kernel-machine regression (BKMR) analysis of single-exposure effects model found that BDE-47 and BDE-99 were positively associated with the risk of malignant neoplasms. The present study not only contributes to the growing evidence regarding the impact of PBDEs on thyroid function but also provides new insights into the association between exposure to certain PBDE congeners and the aggressive pathological parameters of thyroid cancer. Large-scale prospective studies are still needed to support our findings.

Adipose-Derived Stromal Cells and Cancer-Associated Fibroblasts: Interactions and Implications in Tumor Progression.

Adipose-derived stromal cells (ASCs) and cancer-associated fibroblasts (CAFs) play pivotal roles in the tumor microenvironment (TME), significantly influencing cancer progression and metastasis. This review explores the plasticity of ASCs, which can transdifferentiate into CAFs under the influence of tumor-derived signals, thus enhancing their secretion of extracellular matrix components and pro-inflammatory cytokines that promote tumorigenesis. We discuss the critical process of the epithelial-to-mesenchymal transition (EMT) facilitated by ASCs and CAFs, highlighting its implications for increased invasiveness and therapeutic resistance in cancer cells. Key signaling pathways, including the transforming growth factor-β (TGF-β), Wnt/β-catenin, and Notch, are examined for their roles in regulating EMT and CAF activation. Furthermore, we address the impact of epigenetic modifications on ASC and CAF functionality, emphasizing recent advances in targeting these modifications to inhibit their pro-tumorigenic effects. This review also considers the metabolic reprogramming of ASCs and CAFs, which supports their tumor-promoting activities through enhanced glycolytic activity and lactate production. Finally, we outline potential therapeutic strategies aimed at disrupting the interactions between ASCs, CAFs, and tumor cells, including targeted inhibitors of key signaling pathways and innovative immunotherapy approaches. By understanding the complex roles of ASCs and CAFs within the TME, this review aims to identify new therapeutic opportunities that could improve patient outcomes in cancer treatment.

BAFF overexpression in triple-negative breast cancer promotes tumor growth by inducing IL-10-secreting regulatory B cells that suppress anti-tumor T cell responses.

Despite BAFF's (B cell activating factor, BAFF) known influence on B cell survival and proliferation, its specific effects within the tumor microenvironment remain unclear. We aimed to elucidate how BAFF overexpression in breast cancer cells impacts tumor growth and the functions of T and B cells in the tumor microenvironment. BAFF was overexpressed in the 4T1 mouse triple-negative breast cancer cell line, and tumor growth, immune cell infiltration, and activity were assessed in vitro and in vivo using flow cytometry, co-culture assays, and mouse tumor models with B cell depletion. BAFF overexpression in 4T1 cells promoted tumor growth in vivo, suppressed CD8+ T cell activity, and increased IL-10-secreting CD5+ regulatory B cells in tumors. 4T1/BAFF cells directly enhanced IL-10 production in CD5+ B cells via BAFF/BAFF-receptor interactions, and IL-10 from CD5+ B cells inhibited IFN-γ secretion by T cells. B cell depletion partially reversed the tumor-promoting effects of BAFF overexpression. Our study reveals a novel mechanism by which BAFF can foster tumor progression, with the induction of IL-10-secreting regulatory B cells that suppress anti-tumor T cell responses appearing to be a key component of BAFF's tumor-promoting activity. These findings underscore the complex immunomodulatory effects that BAFF exerts in the tumor microenvironment and point to BAFF-induced regulatory B cells as a potential new therapeutic target in breast cancer that warrants further investigation.

Deubiquitinase OTUD7B Regulates Cell Proliferation in Breast Cancer

PurposeThe deubiquitylase OTUD7B plays a facilitates role in lung tumorigenesis through VEGF protein, but its role in breast cancer remains unclear. In the present study, we proposed to explore the role of deubiquitylase OTUD7B in breast cancer. MethodsThe expression of OTUD7B in breast cancer and adjacent tissues was detected. The role of OTUD7B in cell proliferation and invasion of breast cancer cell lines such as MCF-7 and MDA-MB-453 was explored. ResultsOTUD7B is highly expressed in human breast cancer tissues and its higher expression correlates with better survival of patients. Further mechanistic studies reveal that OTUD7B associates with RASGRF1 and PLCE1 to disrupt RAS signaling pathway. Knockdown of OTUD7B results in decreasing levels of RASGRF1 protein, suppression cell growth and invasion in breast cancer. Collectively, our results reveal a previously unappreciated anti-oncogentic role OTUD7B involved in RAS signaling pathway in breast cancer and indicate that deubiquitylases could induce tumor-suppressing or tumor-promoting activities in a cell- and tissue-dependent context.

C1orf106 (INAVA) Is a SMAD3-Dependent TGF-β Target Gene That Promotes Clonogenicity and Correlates with Poor Prognosis in Breast Cancer.

Transforming Growth Factor-β (TGF-β) can have both tumour-promoting and tumour-suppressing activity in breast cancer. Elucidating the key downstream mediators of pro-tumorigenic TGF-β signalling in this context could potentially give rise to new therapeutic opportunities and/or identify biomarkers for anti-TGF-β directed therapy. Here, we identify C1orf106 (also known as innate immunity activator INAVA) as a novel TGF-β target gene which is induced in a SMAD3-dependent but SMAD2/SMAD4-independent manner in human and murine cell lines. C1orf106 expression positively correlates with tumourigenic or metastatic potential in human and murine breast cancer cell line models, respectively, and is required for enhanced migration and invasion in response to TGF-β stimulation. C1orf106 promoted self-renewal and colony formation in vitro and may promote tumour-initiating frequency in vivo. High C1orf106 mRNA expression correlates with markers of aggressiveness and poor prognosis in human breast cancer. Taken together, our findings indicate that C1orf106 may act as a tumour promoter in breast cancer.

NO- and H2S- releasing nanomaterials: A crosstalk signaling pathway in cancer

The gasotransmitters nitric oxide (NO) and hydrogen sulfide (H2S) play important roles not only in maintaining physiological functions, but also in pathological conditions and events. Importantly, these molecules show a complex interplay in cancer biology, demonstrating both tumor-promoting and anti-tumor activities depending on their concentration, flux, and the environmental redox state. Additionally, various cell types respond differently to NO and H2S. These gasotransmitters can be synergistically combined with traditional anticancer treatments such as radiotherapy, immunotherapy, chemotherapy, and phototherapy. Notably, NO, and more recently H2S, have been shown to reverse multidrug resistance. Nanomaterials to deliver NO donors and, to a lesser extent, H2S donors, have emerged as a promising approach for targeted delivery of these gasotransmitters. Nanotechnology has advanced the delivery of anticancer drugs, enhancing efficiency and reducing side effects on non-cancerous cells. This review highlights recent progress in the design of NO and H2S-releasing nanomaterials for anticancer effects. It also explores the interactions between NO and H2S, which are crucial for developing combined therapies and nanomedicines with minimal side effects.

Teleocidin B-4, a PKC Activator, Upregulates Hypoxia-Inducible Factor 1 (HIF-1) Activity by Promoting the Accumulation of HIF-1α Protein via the PKCα/mTORC Signaling Pathway.

Hypoxia-inducible factor 1 (HIF-1) signaling is upregulated in an oxygen-dependent manner under hypoxic conditions. Activation of HIF-1 signaling increases the expression of HIF-1 target genes involved in cell survival, proliferation, and angiogenesis. Therefore, compounds that activate HIF-1 signaling have therapeutic potential in ischemic diseases. Screening for compounds that activate HIF-1 activity identified a microbial metabolite, teleocidin B-4, a PKC activator. Other PKC activators, such as TPA and 10-Me-Aplog-1, also activated HIF-1 activity. PKC activators induced HIF-1α protein accumulation through PKCα/mTORC activation. These results suggest that PKC activators without tumor-promoting activity have potential as therapeutic agents via HIF-1 target gene activation.

Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells and Anticancer Efficacy of Niclosamide with Differential Effects on These Two Processes.

Mutations in p53 and KRAS are seen in most cases of colon cancer. The impact of these mutations on signaling pathways related to cancer growth has been studied in depth, but relatively less is known on their effects on amino acid transporters in cancer cells. This represents a significant knowledge gap because amino acid nutrition in cancer cells profoundly influences macropinocytosis and ferroptosis, two processes with opposing effects on tumor growth. Here, we used isogenic colon cancer cell lines to investigate the effects of p53 deletion and KRAS activation on two amino acid transporters relevant to macropinocytosis (SLC38A5) and ferroptosis (SLC7A11). Our studies show that the predominant effect of p53 deletion is to induce SLC7A11 with the resultant potentiation of antioxidant machinery and protection of cancer cells from ferroptosis, whereas KRAS activation induces not only SLC7A11 but also SLC38A5, thus offering protection from ferroptosis as well as improving amino acid nutrition in cancer cells via accelerated macropinocytosis. Niclosamide, an FDA-approved anti-helminthic, blocks the functions of SLC7A11 and SLC38A5, thus inducing ferroptosis and suppressing macropinocytosis, with the resultant effective reversal of tumor-promoting actions of oncogenic changes in p53 and KRAS. These findings underscore the potential of this drug in colon cancer treatment.

Cutibacterium acnes-derived extracellular vesicles promote tumor growth in renal cell carcinoma.

Bacterial flora are present in various parts of the human body, including the intestine, and are thought to be involved in the etiology of various diseases such as multiple sclerosis, intestinal diseases, cancer, and uterine diseases. In recent years, the presence of bacterial 16S rRNA genes has been revealed in blood, which was previously thought to be a sterile environment, and characteristic blood microbiomes have been detected in various diseases. However, the mechanism and the origin of the bacterial information are unknown. In this study, we performed 16S rRNA metagenomic analysis of bacterial DNA in serum extracellular vesicles from five healthy donors and seven patients with renal cell carcinoma and detected Cutibacterium acnes DNA as a characteristic bacterial DNA in the serum extracellular vesicles of patients with renal cell carcinoma. In addition, C. acnes DNA was significantly reduced in postoperative serum extracellular vesicles from patients with renal cell carcinoma compared with that in preoperative serum extracellular vesicles from these patients and was also detected in tumor tissue and extracellular vesicles from tumor tissue-associated microbiota, suggesting an association between C. acnes extracellular vesicles and renal cell carcinoma. C. acnes extracellular vesicles were taken up by renal carcinoma cells to enhance their proliferative potential. C. acnes extracellular vesicles also exhibited tumor-promoting activity in a mouse model of renal cancer allografts with enhanced angiogenesis. These results suggest that extracellular vesicles released by C. acnes localized in renal cell carcinoma tissues act in a tumor-promoting manner.

Abstract 5888: Novel immune-therapeutic target for lung cancer uncovered by SpliceIO™, an innovative platform that identifies disease-specific alternative splicing

Abstract Alternative splicing (AS) plays a critical role in generating tumor-specific neoantigens targetable through an arsenal of immunotherapeutic modalities. Previous studies have demonstrated tumor-promoting activity of deregulated AS isoforms and mutated splicing factors, both of which increase the yield of neoantigen-encoding AS isoforms. Therefore, the identification of AS isoforms has the potential to produce novel therapeutic targets, especially in lung tumors where splicing deregulation is frequent. Envisagenics has developed SpliceIO, a proprietary software platform for AS-derived neoantigen discovery. SpliceIO uses RNA-seq data to uncover extracellular neoantigens encoded by transmembrane proteins. This predictive ensemble maximizes the value of RNA-seq data to predict fundamental aspects of neoantigen activity, such as protein localization, epitope accessibility, and cancer pathway relevance. Here, we summarize the discovery and validation of novel AS-derived neoantigens identified using SpliceIO in non-small cell lung cancer (NSCLC). Our novel SpliceIO-identified neoantigens in NSCLC were validated following our well-established experimental pipeline. We have confirmed RNA expression of the neoantigen-expressing transcripts in lung cancer cell lines and patient samples using a combination of RT-PCR as well as RNA-ISH. Further, we have validated the membrane-bound extracellular localization of neoantigen-containing isoforms at the protein level using Western blotting, GFP and c-Myc tagged isoform generation, eukaryotic cells transfection, and microscopy. Our top target showed high tumor specificity, heterogeneous distribution in tumor samples, high prevalence, confirmed novel extracellular N-terminal domain, and strong biological relevance in lung cancer. This demonstrates the potential of utilizing RNA splicing for identifying many more membrane associated proteins for tumor specific immunotherapeutic targeting. The combination of computational and experimental approaches to neoantigen identification using SpliceIO allows for novel target discovery amenable for targeted immunotherapeutic development for lung cancer treatment and other indications driven by deregulated AS. Citation Format: Miguel A. Manzanares, Kendall Anderson, Hasan Zumrut, Sakshi Gera, Nayab Habib, Nicole Williams, Shaleigh Stanton, Taylor Floyd, Sanjana Shah, Devon Trahan, Martin Akerman, Gayatri Arun. Novel immune-therapeutic target for lung cancer uncovered by SpliceIO™, an innovative platform that identifies disease-specific alternative splicing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5888.

Association between thyroid disorders and extra-thyroidal cancers, a review.

Thyroid hormone has been shown to have both tumor-promoting and tumor-suppressing actions, which has led to significant debate over its involvement in the development of cancer. Proliferation, apoptosis, invasiveness, and angiogenesis are all aspects of cancer that are affected by the thyroid hormones T3 and T4, according to research conducted in animal models and in vitro experiments. The effects of thyroid hormones on cancer cells are mediated by many non-genomic mechanisms, one of which involves the activation of the plasma membrane receptor integrin αvβ3. Typically, abnormal amounts of thyroid hormones are linked to a higher occurrence of cancer. Both benign and malignant thyroid disorders were found to be associated with an increased risk of extra-thyroidal malignancies, specifically colon, breast, prostate, melanoma, and lung cancers. The purpose of this review was to shed light on this link to define which types of cancer are sensitive to thyroid hormones and, as a result, are anticipated to respond favorably to treatment of the thyroid hormone axis.

Biological Significance of EphB4 Expression in Cancer.

Eph receptors and their Eph receptor-interacting (ephrin) ligands comprise a vital cell communication system with several functions. In cancer cells, there was evidence of bilateral Eph receptor signaling with both tumor-suppressing and tumor-promoting actions. As a member of the Eph receptor family, EphB4 has been linked to tumor angiogenesis, growth, and metastasis, which makes it a viable and desirable target for drug development in therapeutic applications. Many investigations have been conducted over the last decade to elucidate the structure and function of EphB4 in association with its ligand ephrinB2 for its involvement in tumorigenesis. Although several EphB4-targeting drugs have been investigated, and some selective inhibitors have been evaluated in clinical trials. This article addresses the structure and function of the EphB4 receptor, analyses its possibility as an anticancer therapeutic target, and summarises knowledge of EphB4 kinase inhibitors. To summarise, EphB4 is a difficult but potential treatment option for cancers.

Critical and distinct roles of cell type-specific NF-κB2 in lung cancer.

Different from the well-studied canonical NF-κB member RelA, the role of the noncanonical NF-κB member NF-κB2 in solid tumors, and lung cancer in particular, is poorly understood. Here we report that in contrast to the tumor-promoting role of RelA, NF-κB2 intrinsic to lung epithelial and tumor cells had no marked effect on lung tumorigenesis and progression. On the other hand, NF-κB2 limited dendritic cell number and activation in the lung but protected lung macrophages and drove them to promote lung cancer through controlling activation of noncanonical and canonical NF-κB, respectively. NF-κB2 was also required for B cell maintenance and T cell activation. The antitumor activity of lymphocyte NF-κB2 was dominated by the protumor function of myeloid NF-κB2; thus, NF-κB2 has an overall tumor-promoting activity. These studies reveal a cell type-dependent role for NF-κB2 in lung cancer and help understand the complexity of NF-κB action and lung cancer pathogenesis for better design of NF-κB-targeted therapy against this deadliest cancer.

Targeting cancer-derived extracellular vesicles by combining CD147 inhibition with tissue factor pathway inhibitor for the management of urothelial cancer cells

BackgroundExtracellular vesicles (EVs), including microvesicles, hold promise for the management of bladder urothelial carcinoma (BLCA), particularly because of their utility in identifying therapeutic targets and their diagnostic potential using easily accessible urine samples. Among the transmembrane glycoproteins highly enriched in cancer-derived EVs, tissue factor (TF) and CD147 have been implicated in promoting tumor progression. In this in vitro study, we explored a novel approach to impede cancer cell migration and metastasis by simultaneously targeting these molecules on urothelial cancer-derived EVs.MethodsCell culture supernatants from invasive and non-invasive bladder cancer cell lines and urine samples from patients with BLCA were collected. Large, microvesicle-like EVs were isolated using sequential centrifugation and characterized by electron microscopy, nanoparticle tracking analysis, and flow cytometry. The impact of urinary or cell supernatant-derived EVs on cellular phenotypes was evaluated using cell-based assays following combined treatment with a specific CD147 inhibitor alone or in combination with a tissue factor pathway inhibitor (TFPI), an endogenous anticoagulant protein that can be released by low-molecular-weight heparins.ResultsWe observed that EVs obtained from the urine samples of patients with muscle-invasive BLCA and from the aggressive bladder cancer cell line J82 exhibited higher TF activity and CD147 expression levels than did their non-invasive counterparts. The shedding of GFP-tagged CD147 into isolated vesicles demonstrated that the vesicles originated from plasma cell membranes. EVs originating from invasive cancer cells were found to trigger migration, secretion of matrix metalloproteinases (MMPs), and invasion. The same induction of MMP activity was replicated using EVs obtained from urine samples of patients with invasive BLCA. EVs derived from cancer cell clones overexpressing TF and CD147 were produced in higher quantities and exhibited a higher invasive potential than those from control cancer cells. TFPI interfered with the effect when used in conjunction with the CD147 inhibitor, further suppressing homotypic EV-induced migration, MMP production, and invasion.ConclusionsOur findings suggest that combining a CD147 inhibitor with low molecular weight heparins to induce TFPI release may be a promising therapeutic approach for urothelial cancer management. This combination can potentially suppress the tumor-promoting actions of cancer-derived microvesicle-like EVs, including collective matrix invasion.Graphical

Anti-cathepsin D immunotherapy triggers both innate and adaptive anti-tumour immunity in breast cancer.

Triple-negative breast cancer (TNBC) has poorer outcomes than other breast cancers (BC), including HER2+ BC. Cathepsin D (CathD) is a poor prognosis marker overproduced by BC cells, hypersecreted in the tumour microenvironment with tumour-promoting activity. Here, we characterized the immunomodulatory activity of the anti-CathD antibody F1 and its improved Fab-aglycosylated version (F1M1) in immunocompetent mouse models of TNBC (C57BL/6 mice harbouring E0771 cell grafts) and HER2-amplified BC (BALB/c mice harbouring TUBO cell grafts). CathD expression was evaluated by western blotting and immunofluorescence, and antibody binding to CathD by ELISA. Antibody anti-tumour efficacy was investigated in mouse models. Immune cell recruitment and activation were assessed by immunohistochemistry, immunophenotyping, and RT-qPCR. F1 and F1M1 antibodies remodelled the tumour immune landscape. Both antibodies promoted innate antitumour immunity by preventing the recruitment of immunosuppressive M2-polarized tumour-associated macrophages (TAMs) and by activating natural killer cells in the tumour microenvironment of both models. This translated into a reduction of T-cell exhaustion markers in the tumour microenvironment that could be locally supported by enhanced activation of anti-tumour antigen-presenting cell (M1-polarized TAMs and cDC1 cells) functions. Both antibodies inhibited tumour growth in the highly-immunogenic E0771 model, but only marginally in the immune-excluded TUBO model, indicating that anti-CathD immunotherapy is more relevant for BC with a high immune cell infiltrate, as often observed in TNBC. Anti-CathD antibody-based therapy triggers the anti-tumour innate and adaptive immunity in preclinical models of BC and is a promising immunotherapy for immunogenic TNBC.

FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis

FGF19 hormone has pleiotropic metabolic functions, including the modulation of insulin sensitivity, glucose/lipid metabolism and energy homeostasis. On top of its physiological metabolic role, FGF19 has been identified as a potentially targetable oncogenic driver, notably in hepatocellular carcinoma (HCC). Nevertheless, FGF19 remained an attractive candidate for treatment of metabolic disease, prompting the development of analogs uncoupling its metabolic and tumor-promoting activities. Using pre-clinical mice models of somatic mutation driven HCC, we assessed the oncogenicity of FGF19 in combination with frequent HCC tumorigenic alterations: p53 inactivation, CTNNB1 mutation, CCND1 or MYC overexpression. Our data revealed a strong oncogenic cooperation between FGF19 and MYC. Most importantly, we show that this oncogenic synergy is conserved with a FGF19-analog Aldafermin (NGM282), designed to solely mimic the hormone’s metabolic functions. In particular, even a short systemic treatment with recombinant proteins triggered rapid appearance of proliferative foci of MYC-expressing hepatocytes. The fact that FGF19 analog Aldafermin is not fully devoid of the hormone’s oncogenic properties raises concerns in the context of its potential use for patients with damaged, mutation-prone liver.

DNA-PK-Mediated Cytoplasmic DNA Sensing Stimulates Glycolysis to Promote Lung Squamous Cell Carcinoma Malignancy and Chemoresistance.

DNA-PK is a cytoplasmic DNA sensor that activates ZAK/AKT/mTOR signaling and boosts glycolysis to enhance malignancy and chemoresistance of lung squamous cell carcinoma.

ATP1A1 is a promising new target for melanoma treatment and can be inhibited by its physiological ligand bufalin to restore targeted therapy efficacy

Despite advancements in treating metastatic melanoma, many patients exhibit resistance to targeted therapies. Our study focuses on ATP1A1, a sodium pump subunit associated with cancer development. We aimed to assess ATP1A1 prognostic value in melanoma patients and examine the impact of its ligand, bufalin, on melanoma cell lines in vitro and in vivo. High ATP1A1 expression (IHC) correlated with reduced overall survival in melanoma patients. Resistance to BRAF inhibitor was linked to elevated ATP1A1 levels in patient biopsies (IHC, qPCR) and cell lines (Western blot, qPCR). Additionally, high ATP1A1 mRNA expression positively correlated with differentiation/pigmentation markers based on data from The Cancer Genome Atlas (TCGA) databases and Verfaillie proliferative gene signature analysis. Bufalin specifically targeted ATP1A1 in caveolae, (proximity ligation assay) and influenced Src phosphorylation (Western blot), thereby disrupting multiple signaling pathways (phosphokinase array). In vitro, bufalin induced apoptosis in melanoma cell lines by acting on ATP1A1 (siRNA experiments) and, in vivo, significantly impeded melanoma growth using a nude mouse xenograft model with continuous bufalin delivery via an osmotic pump. In conclusion, our study demonstrates that ATP1A1 could serve as a prognostic marker for patient survival and a predictive marker for response to BRAF inhibitor therapy. By targeting ATP1A1, bufalin inhibited cell proliferation, induced apoptosis in vitro, and effectively suppressed tumor development in mice. Thus, our findings strongly support ATP1A1 as a promising therapeutic target, with bufalin as a potential agent to disrupt its tumor-promoting activity.

Rewiring the T cell-suppressive cytokine landscape of the tumor microenvironment: a new frontier for precision anti-cancer therapy.

T lymphocytes that infiltrate the tumor microenvironment (TME) often fail to function as effective anti-cancer agents. Within the TME, cell-to-cell inhibitory interactions play significant roles in dampening their anti-tumor activities. Recent studies have revealed that soluble factors released in the TME by immune and non-immune cells, as well as by tumor cells themselves, contribute to the exacerbation of T cell exhaustion. Our understanding of the cytokine landscape of the TME, their interrelationships, and their impact on cancer development is still at its early stages. In this review, we aim to shed light on Interleukin (IL) -6, IL-9, and IL-10, a small group of JAK/STAT signaling-dependent cytokines harboring T cell-suppressive effects in the TME and summarize their mechanisms of action. Additionally, we will explore how advancements in scientific research can help us overcoming the obstacles posed by cytokines that suppress T cells in tumors, with the ultimate objective of stimulating further investigations for the development of novel therapeutic strategies to counteract their tumor-promoting activities.

Non B Cell-Derived Immunoglobulins in Lung Epithelial Cells and Lung Cancer.

As the locus for air exchange, lung tissue is perpetually exposed to a significant quantity of foreign pathogens. Consequently, lung has developed a refined and intricate immune system. Beyond their physical and chemical barrier roles, lung epithelial cells can contribute to immune defence through the expression of Toll-like receptors (TLRs) and other pattern recognition receptors, along with the secretion of cytokines. Emerging evidence demonstrates that lung epithelial cells can generate and secrete immunoglobulins (Igs), including IgM, IgA, or IgG, thus performing antibody function. Moreover, malignantly transformed lung epithelial cells have been discovered to produce high levels of Ig, predominantly IgG, which do not fulfill the role of antibodies, but instead carries out tumour-promoting activity. Structural analysis has indicated that the biological activity of IgG produced by lung cancer cells differs from that of Igs produced by normal lung epithelial cells due to the unique glycosylation modification. Specifically, the sialylated IgG (SIA-IgG), characterised by a non-traditional N-glycosylation modification at the Asn162 site of Igγ CH1, is highly expressed in tumour stem cells. It has been demonstrated that SIA-IgG relies on this unique sialylation modification to promote tumorigenesis, metastasis, and immune evasion. Current results have proven that the Ig produced by lung epithelial cells has multifaceted biological activities, including immune defence functions under physiological conditions, while acquiring tumour-promoting activity during malignant transformation. These insights possess potential for the diagnosis and treatment of lung cancer as novel biomarkers and targets.