Prognostic Value of KRAS Mutations in Relation to PDL1 Expression and Immunotherapy Treatment in Adenocarcinoma and Squamous Cell Carcinoma Patients: A Greek Cohort Study.

BACKGROUND: Factors that could predict which patients will benefit from Immune Checkpoint Inhibitors (ICIs) are not fully understood. This study aimed to investigate the prognostic value of KRAS biomarker in patients with advanced non-small cell lung cancer (NSCLC) in relation to clinical characteristics, treatment response and PDL1 expression. PATIENTS AND METHODS: The study included 100 patients with NSCLC who received immunotherapy with or without chemotherapy as 1st line treatment. In biopsy samples, the PDL1 biomarker expression rate and somatic mutations of KRAS gene were determined. RESULTS: The mean age of the patients was 67 ± 8 years. Patients were all male and 66% were found with adenocarcinoma whereas 34% with squamous cell carcinoma. The KRAS G12C mutation was found with the highest percentage (73%). In the Kaplan-Meier survival analysis, patients with PDL1 > 49% in combination with a negative KRAS result had a median overall survival of 40 months compared to patients with a positive KRAS result (9 months, p < 0.05). In addition, patients diagnosed with adenocarcinoma, PDL1 < 49% and negative KRAS result had a median overall survival of 39 months compared to patients with a positive result (28 months, p < 0.05). CONCLUSIONS: Our study suggests that the presence of KRAS mutations in advanced NSCLC patients has a poor prognostic value, regardless of their PDL1 expression values, after receiving immunotherapy as first-line treatment.

Association of Fetal Lung Development Disorders with Adult Diseases: A Comprehensive Review.

Fetal lung development is a crucial and complex process that lays the groundwork for postnatal respiratory health. However, disruptions in this delicate developmental journey can lead to fetal lung development disorders, impacting neonatal outcomes and potentially influencing health outcomes well into adulthood. Recent research has shed light on the intriguing association between fetal lung development disorders and the development of adult diseases. Understanding these links can provide valuable insights into the developmental origins of health and disease, paving the way for targeted preventive measures and clinical interventions. This review article aims to comprehensively explore the association of fetal lung development disorders with adult diseases. We delve into the stages of fetal lung development, examining key factors influencing fetal lung maturation. Subsequently, we investigate specific fetal lung development disorders, such as respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), congenital diaphragmatic hernia (CDH), and other abnormalities. Furthermore, we explore the potential mechanisms underlying these associations, considering the role of epigenetic modifications, transgenerational effects, and intrauterine environmental factors. Additionally, we examine the epidemiological evidence and clinical findings linking fetal lung development disorders to adult respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), and other respiratory ailments. This review provides valuable insights for healthcare professionals and researchers, guiding future investigations and shaping strategies for preventive interventions and long-term care.

Expression patterns and clinical implications of PDL1 and DLL3 biomarkers in small cell lung cancer retrospectively studied: Insights for therapeutic strategies and survival prediction.

Lung cancer is a leading cause of cancer-related deaths globally, includes small cell lung cancer (SCLC), characterized by its aggressive nature and advanced disease at diagnosis. However, the identification of reliable biomarkers for SCLC has proven challenging, as no consistent predictive biomarker has been established. Nonetheless, certain tumor-associated antigens, including programmed death-ligand 1 (PDL1) and Delta-Like Ligand 3 (DLL3), show promise for targeted antibody-based immunotherapy. To ensure optimal patient selection, it remains crucial to comprehend the relationship between PDL1 and DLL3 expression and clinicopathological characteristics in SCLC. In this study, we investigated the expression patterns of PDL1 and DLL3 biomarkers in endobronchial samples from 44 SCLC patients, examining their association with clinical characteristics and survival. High PDL1 expression (>1%) was observed in 14% of patients, while the majority the SCLC patients (73%) exhibited high DLL3 expression (>75%). Notably, we found a positive correlation between high PDL1 expression (>1%) and overall survival. However, we did not observe any significant differences in the biomarkers expression concerning age, sex, disease status, smoking status, or distant metastases. Further subgroup analysis revealed that a high co-expression of both PDL1 (>1%) and DLL3 (100%) antigens was associated with improved overall survival. This suggests that SCLC expressing PDL1 and DLL3 antigens may exhibit increased sensitivity to therapy, indicating their potential as therapeutic targets. Thus, our findings provide novel insights into the simultaneous evaluation of PDL1 and DLL3 biomarkers in SCLC patients. These insights have significant clinical implications for therapeutic strategies, survival prediction, and development of combination immunotherapies.

Effect of Intraperitoneal Chemotherapy with Regorafenib on IL-6 and TNF-α Levels and Peritoneal Cytology: Experimental Study in Rats with Colorectal Peritoneal Carcinomatosis.

Cytoreductive surgery (CRS), combined with hyperthermic intraperitoneal chemotherapy, has significantly improved survival outcomes in patients with peritoneal carcinomatosis from colorectal cancer (CRC). Regorafenib is an oral agent administered in patients with refractory metastatic CRC. Our aim was to investigate the outcomes of intraperitoneal administration of regorafenib for intraperitoneal chemotherapy (IPEC) or/and CRS in a rat model of colorectal peritoneal metastases regarding immunology and peritoneal cytology. A total of 24 rats were included. Twenty-eight days after carcinogenesis induction, rats were randomized into following groups: group A: control group; group B: CRS only; group C: IPEC only; and group D: CRS + IPEC. On day 56 after carcinogenesis, euthanasia and laparotomy were performed. Serum levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) as well as peritoneal cytology were investigated. Groups B and D had statistically significant lower mean levels of IL-6 and TNF-α compared to groups A and C, but there was no significant difference between them. Both B and D groups presented a statistically significant difference regarding the rate of negative peritoneal cytology, when compared to the control group, but not to group C. In conclusion, regorafenib-based IPEC, combined with CRS, may constitute a promising tool against peritoneal carcinomatosis by altering the tumor microenvironment.

Prognostic Value of Serum Biomarkers in Patients with Idiopathic Pulmonary Fibrosis in Relation to Disease Progression.

BACKGROUND: The aim of this present study was to determine serum biomarker levels and their correlation with respiratory function and the clinical course of patients with idiopathic pulmonary fibrosis (IPF). MATERIALS AND METHODS: This study included 72 IPF patients, according to the ATS/ERS criteria, in whom antifibrotic treatment was initiated. Blood samples were taken, and serum biomarkers, such as KL-6, SP-D, CCL18, CXCL13, VEGF-A, IL-8, IGFBP-1, IGFBP-2, IGFBP-7 and ICAM-1 were measured using ELISA methodology. Pulmonary function tests (FVC, TLC, DLCO-% pred) were determined at baseline and after 12 and 24 months and analyzed in correlation with the biomarkers. RESULTS: The majority of patients (mean age 72 ± 6 years) were men (83%). The FVC and DLCO values at the 12-month follow-up were found to be statistically decreased in deceased patients (p < 0.05). The SP-D (p < 0.001) and the IGFBP-1 (p = 0.021) levels were found to be increased at the 1-year follow-up in deceased patients, and similarly, the SP-D (p = 0.005) and ICAM-1 (p = 0.043) levels at the 2-year follow-up. A chi-square test revealed that 70% of the category IV GAP index was found with cut-off elevated levels of a biomarker combination (KL-6, SP-D, VEGF-A) from the ROC curve analysis (p < 0.05). CONCLUSION: This study provides evidence, for the first time in a Greek population, of the possibility of using a combination of KL-6, SP-D, and VEGF-A serum levels along with the GAP index.

Open and Closed Triple Inhaler Therapy in Patients with Uncontrolled Asthma.

Long-acting muscarinic antagonists (LAMAs) are a class of inhalers that has recently been included as add-on therapy in the GINA guidelines, either in a single inhaler device with inhaled corticosteroids plus long-acting ß2-agonists (ICS + LABA) (closed triple inhaler therapy) or in a separate one (open triple inhaler therapy). This review summarizes the existing evidence on the addition of LAMAs in patients with persistently uncontrolled asthma despite ICS + LABA treatment based on clinical efficacy in the reduction of asthma symptoms and exacerbations, the improvement in lung function, and its safety profile.

Recent insights in the role of biomarkers in severe asthma management.

Contemporary asthma management requires a proactive and individualized approach, combining precision diagnosis and personalized treatment. The introduction of biologic therapies for severe asthma to everyday clinical practice, increases the need for specific patient selection, prediction of outcomes and monitoring of these costly and long-lasting therapies. Several biomarkers have been used in asthma in disease identification, prediction of asthma severity and prognosis, and response to treatment. Novel advances in the area of personalized medicine regarding disease phenotyping and endotyping, encompass the development and application of reliable biomarkers, accurately quantified using robust and reproducible methods. The availability of powerful omics technologies, together with integrated and network-based genome data analysis, and microbiota changes quantified in serum, body fluids and exhaled air, will lead to a better classification of distinct phenotypes or endotypes. Herein, in this review we discuss on currently used and novel biomarkers for the diagnosis and treatment of asthma.

The feasibility and effect of intraperitoneal administration of regorafenib on peritoneal carcinomatosis from colorectal cancer in the rat.

AIM: Our goal was to investigate the potential use and efficacy of regorafenib for IPEC in an animal model of colorectal derived peritoneal metastases. Twenty four male rats were included. Carcinogenesis was induced in all rats through intraperitoneal injection of cancer. MATERIAL AND METHODS: Cells at T0. At T1(Day 28) they were randomly allocated 1:1:1:1 into 4 groups and underwent median laparotomy and the corresponding intervention. Specifically, Group A: no other intervention; Group B: cytoreductive surgery; Group C: intraperitoneal chemotherapy with regorafenib; and Group D: cytoreductive surgery and intraperitoneal chemotherapy with regorafenib. At T2 (Day 56) rats were euthanized and laparotomy was performed for further investigation. The primary outcome was the experimental Peritoneal Cancer Index (ePCI) at T2. Secondary outcomes include relative change of body weight between T1 and T2, weight of the ascites, anastomotic leak/peritonitis and death. RESULTS: The ePCI was significantly lower in Group D as opposed to all other groups. Comparing Group C versus Group A we found a trend towards lesser tumor progression, but no significant difference. Growth of rats in Group D was significantly least affected compared to all other groups. Animals undergoing CRS in Group B developed less ascites than Group A and C. Less ascites was found in Group D compared to Group A and C. CONCLUSIONS: Intraperitoneal chemotherapy with regorafenib combined with cytoreductive surgery may impair metastases' progression. KEY WORDS: Regorafenib, Chemotherapy, Cytoreductive surgery, Colorectal cancer, Intraperitoneal injection.

Engineered Hybrid Treg-Targeted Nanosomes Restrain Lung Immunosuppression by Inducing Intratumoral CD8+T Cell Immunity.

Introduction: Tumor immunotherapy is a key therapeutic paradigm for the treatment of several malignancies. However, in metastatic lung cancer, classical immunotherapy regimes are ineffective due to regulatory T cell (Treg)-related immunosuppression and tumor relapse. Materials: To address this issue, we designed specific biocompatible Treg-targeted nanocarriers (NCs) as a model of immune-based nanotherapy, in order to target Treg-related immunosuppression in the lung tumor microenvironment. This is achieved through the combination of Dasatinib and Epacadostat integrated into biodegradable nanosomes which can inhibit and reverse Treg-supporting immunosuppression. Flow cytometry and immunofluorescence analysis, PET/CT scan, PTT/PA imaging and the Balb/c tumor model were used to explore the anti-tumor effect of Treg-targeted NCs both in vitro and in vivo. Results: Findings reveal that NC treatment triggered substantial tumor cell apoptosis and drastically decreased tumor volume followed by downregulation of Ki-67 antigen expression, respectively. Drug circulation time was also increased as shown by biodistribution analysis accompanied by greater accumulation in lung and peripheral tissues. Intratumoral Th1 cytokines' expression was also increased, especially TNF-A, IL-12 by 42%, and IL-6 by 18% compared to PBS treatment. In addition, the presence of mature CD80+/CD86+dendritic cells (DCs) revealed T cell enrichment and a decline in MDSC infiltration and myeloid subsets. Interestingly, a significant decline of Gr/CD11b myeloid cell population in blood and tissue samples was also observed. This immune activation can be attributed to the enhanced PTT efficiency and tumor targeting ability of the nanospheres which under near infrared (NIR) exposure can prompt highly efficient tumor ablation. We also demonstrated their therapeutic efficacy against 4T1 metastatic breast cancer model. Additionally, the photothermal therapy in combination with PD-L1 checkpoint blockade therapy exerted long-term tumor control over both primary and distant tumors. Discussion: Overall, our findings present a novel nano-enabled platform for the inhibition of Treg-dependent immunosuppression in NSCLC and provide a novel nanotherapeutic strategy for the treatment of metastatic neoplasia.

Clinical, imaging and functional determinants of sarcoidosis phenotypes in a Greek population.

Background: The aim of the present study was the application of the latest phenotype recommendations in Greek patients, in order to identify specific clinical, imaging and spirometric characteristics, at initial diagnosis of sarcoidosis, related to disease phenotypes. Methods: Our cohort included 147 patients coming from Northern Greece, recruited from the Outpatient Sarcoidosis Clinic, of Aristotle University of Thessaloniki. The observation period was 5 years. The Scadding staging system and the World Association of Sarcoidosis and other Granulomatous Disorders (WASOG) Clinical Outcome Status instrument were used. Phenotypes were defined by the latest DELPHI consensus recommendations. Results: The following clinical phenotypes were identified: asymptomatic 59%, acute 14.3%, chronic 12.9% and advanced 33.3%. The observed phenotypes were not related to Scadding stages. Lung function decline was in line with phenotype severity. The presence of fibrosis to any extent upon diagnosis differed among phenotypes (asymptomatic 13.8%, acute 38.1%, chronic 57.9%, advanced 61.2%, P<0.001) and was common for relapsing patients (P<0.001). In spontaneously remitting patients, fibrosis upon diagnosis was found less often than in non-remitting patients (P<0.001). Renal involvement was more frequently found in the advanced phenotype (P=0.032). Skin involvement was more common for patients with acute onset (P<0.001) and spontaneous remission (P=0.012). Ocular involvement was mainly found in relapsing patients (P<0.001). Conclusions: In our cohort, sarcoidosis clinical phenotypes have certain clinical, imaging and functional characteristics, at initial diagnosis of the disease, which could be assessed in everyday practice.

Eosinophilic Asthma, Phenotypes-Endotypes and Current Biomarkers of Choice.

Asthma phenotyping and endotyping are constantly evolving. Currently, several biologic agents have been developed towards a personalized approach to asthma management. This review will focus on different eosinophilic phenotypes and Th2-associated endotypes with eosinophilic inflammation. Additionally, airway remodeling is analyzed as a key feature of asthmatic eosinophilic endotypes. In addition, evidence of biomarkers is examined with a predictive value to identify patients with severe, uncontrolled asthma who may benefit from new treatment options. Finally, there will be a discussion on the results from clinical trials regarding severe eosinophilic asthma and how the inhibition of the eosinophilic pathway by targeted treatments has led to the reduction of recurrent exacerbations.

Epigenetic editing and tumor-dependent immunosuppressive signaling in head and neck malignancies.

Head and neck cancer (HNC) comprises a heterogeneous variety of malignant tumors, characterized by a relatively high tumor mutation burden. Previous data have revealed that immune system dysfunction appears to serve a key role in the development and progression of HNC and established immunosuppression is vital for evading the host immune response. Despite progress in chemotherapy and radiotherapy, the survival rate of patients with HNC is still low. Therefore, the present review discusses the development of novel immunotherapy approaches based on the various immune cell signaling routes that trigger drug resistance and immunosuppression. Additionally, the present review discusses the epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling and non-coding RNAs that drive and support HNC progression. Furthermore, the role of cancer-associated fibroblasts, tumor macrophages and myeloid cells in tumor-related immunosuppression are considered. Specifically, the molecular immune-related mechanisms in the tumor microenvironment, which lead to decreased drug sensitivity and tumor relapse, and strategies for reversing drug resistance and targeting immunosuppressive tumor networks are discussed. Deciphering these molecular mechanisms is essential for preclinical and clinical investigations in order to enhance therapeutic efficacy. Furthermore, an improved understanding of these immune cell signaling pathways that drive immune surveillance, immune-driven inflammation and tumor-related immunosuppression is necessary for future personalized HNC-based therapeutic approaches.

BALF and BLOOD NK- cells in different stages of pulmonary sarcoidosis.

BACKGROUND AND OBJECTIVE: Data on natural killer (NK)- and natural killer T (NKT)- like cells in the immunopathogenesis of sarcoidosis remain limited. The aim was to assess NK- and NKT-like cells across different stages in bronchoalveolar lavage (BALF) versus peripheral blood (PB) in comparison to controls. METHODS: Forty four patients (32 women and 12 men, mean age 46.6±14.4 years) with biopsy-proven sarcoidosis and 10 healthy individuals (6 women, 4 men mean age 52.6±19.1 years) were submitted to BALF. Total cells and cell differentials were counted, while CD45+, CD3+, CD4+, CD8+, CD19+, CD3-CD16/56 (NK cells) and CD3+CD16/56+ (NKT-like cells) were determined by dual flow cytometry in BALF and PB. RESULTS: A significantly lower percentage of both NK and NKT-like cells was observed in BALF of controls and sarcoid patients (SP) compared to PB. Both BALF NK and NKT-cell counts were significantly higher in SP than in controls (NK: p=0.046, NKT-like: p=0.012) In addition BALF NK cell percentage differed among sarcoidosis stages (p=0.005). In PB NK-cell count was lower in sarcoidosis patients but the difference did not reach statistical significance. Also, in sarcoid patients' BALF NK-cell percentage negatively correlated with lymphocyte percentage (r=-0.962, p<0.001). CONCLUSIONS: The increased count of BALF NK and NKT-like cells in sarcoidosis compared to controls along with the increase of NK cells with stage progression are in line with a growing number of investigations suggesting the involvement of NK- and NKT-like cells in the pathogenesis of sarcoidosis.

Electronic Cigarettes and Asthma: What Do We Know So Far?

Electronic cigarettes (EC) are a novel product, marketed as an alternative to tobacco cigarette. Its effects on human health have not been investigated widely yet, especially in specific populations such as patients with asthma. With this review, we use the existing literature in order to answer four crucial questions concerning: (1) ECs' role in the pathogenesis of asthma; (2) ECs' effects on lung function and airway inflammation in patients with asthma; (3) ECs' effects on asthma clinical characteristics in asthmatics who use it regularly; and (4) ECs' effectiveness as a smoking cessation tool in these patients. Evidence suggests that many EC compounds might contribute to the pathogenesis of asthma. Lung function seems to deteriorate by the use of EC in this population, while airway inflammation alters, with the aggravation of T-helper-type-2 (Th2) inflammation being the most prominent but not the exclusive effect. EC also seems to worsen asthma symptoms and the rate and severity of exacerbations in asthmatics who are current vapers, whilst evidence suggests that its effectiveness as a smoking cessation tool might be limited. Asthmatic patients should avoid using EC.

Kras-driven intratumoral heterogeneity triggers infiltration of M2 polarized macrophages via the circHIPK3/PTK2 immunosuppressive circuit.

Intratumoral heterogeneity in lung cancer is essential for evasion of immune surveillance by tumor cells and establishment of immunosuppression. Gathering data reveal that circular RNAs (circRNAs), play a role in the pathogenesis and progression of lung cancer. Particularly Kras-driven circRNA signaling triggers infiltration of myeloid-associated tumor macrophages in lung tumor microenvironment thus establishing immune deregulation, and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras signaling in circRNA-related immunosuppression and its involvement in tumoral chemoresistance. The expression pattern of circRNAs HIPK3 and PTK2 was determined using quantitative polymerase chain reaction (qPCR) in lung cancer patient samples and cell lines. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. M2 macrophage polarization and MDSC subset analysis (Gr1-/CD11b-, Gr1-/CD11b+) were determined by flow cytometry. Tumor growth and metastatic potential were determined in vivo in C57BL/6 mice. Findings reveal intra-epithelial CD163+/CD206+ M2 macrophages to drive Kras immunosuppressive chemoresistance through myeloid differentiation. In particular, monocytic MDSC subsets Gr1-/CD11b-, Gr1-/CD11b+ triggered an M2-dependent immune response, creating an immunosuppressive tumor-promoting network via circHIPK3/PTK2 enrichment. Specifically, upregulation of exosomal cicHIPK3/PTK2 expression prompted Kras-driven intratumoral heterogeneity and guided lymph node metastasis in C57BL/6 mice. Consequent co-inhibition of circPTK2/M2 macrophage signaling suppressed lung tumor growth along with metastatic potential and prolonged survival in vivo. Taken together, these results demonstrate the key role of myeloid-associated macrophages in sustaining lung immunosuppressive neoplasia through circRNA regulation and represent a potential therapeutic target for clinical intervention in metastatic lung cancer.

Increased monocyte count and red cell distribution width as prognostic biomarkers in patients with Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) represents a chronic lung disease with unpredictable course. METHODS: We aimed to investigate prognostic performance of complete blood count parameters in IPF. Treatment-naïve patients with IPF were retrospectively enrolled from two independent cohorts (derivation and validation) and split into subgroups (high and low) based on median baseline monocyte count and red cell distribution width (RDW). RESULTS: Overall, 489 patients (derivation cohort: 300, validation cohort: 189) were analyzed. In the derivation cohort, patients with monocyte count ≥ 0.60 K/µL had significantly lower median FVC%pred [75.0, (95% CI 71.3-76.7) vs. 80.9, (95% CI 77.5-83.1), (P = 0.01)] and DLCO%pred [47.5, (95% CI 44.3-52.3) vs. 53.0, (95% CI 48.0-56.7), (P = 0.02)] than patients with monocyte count < 0.60 K/µL. Patients with RDW ≥ 14.1% had significantly lower median FVC%pred [75.5, (95% CI 71.2-79.2) vs. 78.3, (95% CI 76.0-81.0), (P = 0.04)] and DLCO%pred [45.4, (95% CI 43.3-50.5) vs. 53.0, (95% CI 50.8-56.8), (P = 0.008)] than patients with RDW < 14.1%. Cut-off thresholds from the derivation cohort were applied to the validation cohort with similar discriminatory value, as indicated by significant differences in median DLCO%pred between patients with high vs. low monocyte count [37.8, (95% CI 35.5-41.1) vs. 45.5, (95% CI 41.9-49.4), (P < 0.001)] and RDW [37.9, (95% CI 33.4-40.7) vs. 44.4, (95% CI 41.5-48.9), (P < 0.001)]. Patients with high monocyte count and RDW of the validation cohort exhibited a trend towards lower median FVC%pred (P = 0.09) and significantly lower median FVC%pred (P = 0.001), respectively. Kaplan-Meier analysis in the derivation cohort demonstrated higher all-cause mortality in patients with high (≥ 0.60 K/µL) vs. low monocyte count (< 0.60 K/µL) [HR 2.05, (95% CI 1.19-3.53), (P = 0.01)]. CONCLUSIONS: Increased monocyte count and RDW may represent negative prognostic biomarkers in patients with IPF.

Treg-dependent immunosuppression triggers effector T cell dysfunction via the STING/ILC2 axis.

Lung cancer remains the leading cause of cancer-related deaths and despite extensive research, the survival rate of lung cancer patients remains significantly low. Recent data reveal that aberrant Kras signaling drives regulatory T cells (Tregs) present in lung tumor microenvironment to establish immune deregulation and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras in Treg-related immunosuppression and its involvement in tumor-associated metabolic reprogramming. Findings reveal Tregs to prompt GATA3/NOS2-related immunosuppression via STING inhibition which triggers a decline in CD4+ T infiltration, and a subsequent increase in lung metastatic burden. Enhanced Treg expression was also associated with low T/MDSC ratio through restriction of CD8+CD44+CD62L- T effector cells, contributing to a tumor-promoting status. Specifically, TIM3+/LAG3+ Tregs prompted Kras-related immunosuppressive chemoresistance and were associated with T cell dysfunction. This Treg-dependent immunosuppression correlated with CD8 T cell exhaustion phenotype and ILC2 augmentation in mice. Moreover, enhanced Treg expression promoted activation-induced cell death (AICD) of T lymphocytes and guided lymph node metastasis in vivo. Overall, these findings demonstrate the multifaceted roles of Tregs in sustaining lung immunosuppressive neoplasia through tumor microenvironment remodeling and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.

Exosomal lncRNA PCAT-1 promotes Kras-associated chemoresistance via immunosuppressive miR-182/miR-217 signaling and p27/CDK6 regulation.

Immunosuppressive chemoresistance is a major burden in lung cancer. Recent data reveal that long noncoding RNAs (lncRNAs) present in the lung tumor microenvironment are implicated in chemoresistant-related immune deregulation, and metastasis but their exact pathogenic role is still unknown. In this study, we investigate the role of lncRNA PCAT-1 in chemoresistant immunosuppression and its involvement in tumor stroma remodeling. Findings reveal PCAT-1 to regulate Kras-related lung chemoresistance through increased expression of the immunosuppressive micrornas miR-182/miR217 in lung tissues, thus promoting a pre-metastatic niche formation and a subsequent increase in lung metastatic burden. Elevated expression of PCAT-1 negative regulates p27/CDK6 expression by inducing G0/G1 cell cycle arrest through AMPK augmentation, contributing to a tumor-promoting status. Furthermore, PCAT-1 triggered fibroblast differentiation followed by CAF/myofibroblast secretion in TME triggering a CD133/SOX2-related stem cell phenotype. Subsequent PCAT-1 knockdown impaired CAF-mediated stromal activation, and reversed chemoresistance and tumor growth in vivo. Overall, these findings demonstrate the versatile roles of PCAT-1 in sustaining lung immunosuppressive neoplasia through tumor microenvironment remodeling and provide new opportunities for effective metastasis inhibition, especially in chemoresistant tumors.