MAIT cells are associated with responsiveness to neoadjuvant immunotherapy in COPD-associated NSCLC.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) and chronic obstructive pulmonary disease (COPD) experience worse clinical outcomes but respond better to immunotherapy than patients with NSCLC without COPD. Mucosal-associated invariant T (MAIT) cells, a versatile population of innate immune T lymphocytes, have a crucial function in the response to infection and tumors. This study investigated the distribution of MAIT cells in COPD-associated NSCLC and their involvement in the immune response. METHODS: Flow cytometry, immunohistochemistry, and immunofluorescence were performed on tissue samples of patients with NSCLC, with or without COPD, treated with or without anti-programmed death 1 (PD1) immunotherapy. MAIT cells were stimulated with 5-OP-RU using a mouse subcutaneous tumor model. RESULTS: Tumors contained significantly more MAIT cells than paraneoplastic tissues, and CD8+ MAIT cells accounted for more than 90% of these cells. Patients with NSCLC and COPD had higher CD8+ MAIT cell counts than those with NSCLC without COPD. Additionally, patients with NSCLC and COPD displayed reduced expression of the activation marker, CD69, and functional markers, granzyme B (GZMB) and interferon γ (IFNγ), and higher expression of the immune exhaustion marker, PD1. Among patients who received immunotherapy, the proportion with a complete or partial response was higher in those with COPD than in those without COPD. In patients with NSCLC and COPD, the major pathologic response (MPR) group had higher MAIT levels than those in the no major pathologic response (NPR) group. In the mouse subcutaneous tumor model stimulation of MAIT cells using 5-OP-RU enhanced the antitumor effects of anti-PD1. CONCLUSIONS: In patients with NSCLC and COPD, response to immunotherapy is associated with accumulation of CD8+ MAIT cells showing immune exhaustion. These findings may contribute to innovative approaches for immunotherapy targeting CD8+ MAIT cells.

Down-regulated HHLA2 enhances neoadjuvant immunotherapy efficacy in patients with non-small cell lung cancer (NSCLC) with chronic obstructive pulmonary disease (COPD).

BACKGROUND: Emerging data suggested a favorable outcome in advanced non-small cell lung cancer (NSCLC) with chronic obstructive pulmonary disease (COPD) patients treated by immunotherapy. The objective of this study was to investigate the effectiveness of neoadjuvant immunotherapy among NSCLC with COPD versus NSCLC without COPD and explore the potential mechanistic links. PATIENTS AND METHODS: Patients with NSCLC receiving neoadjuvant immunotherapy and surgery at Shanghai Pulmonary Hospital between November 2020 and January 2023 were reviewed. The assessment of neoadjuvant immunotherapy's effectiveness was conducted based on the major pathologic response (MPR). The gene expression profile was investigated by RNA sequencing data. Immune cell proportions were examined using flow cytometry. The association between gene expression, immune cells, and pathologic response was validated by immunohistochemistry and single-cell data. RESULTS: A total of 230 NSCLC patients who received neoadjuvant immunotherapy were analyzed, including 60 (26.1%) with COPD. Multivariate logistic regression demonstrated that COPD was a predictor for MPR after neoadjuvant immunotherapy [odds ratio (OR), 2.490; 95% confidence interval (CI), 1.295-4.912; P = 0.007]. NSCLC with COPD showed a down-regulation of HERV-H LTR-associating protein 2 (HHLA2), which was an immune checkpoint molecule, and the HHLA2low group demonstrated the enrichment of CD8+CD103+ tissue-resident memory T cells (TRM) compared to the HHLA2high group (11.9% vs. 4.2%, P = 0.013). Single-cell analysis revealed TRM enrichment in the MPR group. Similarly, NSCLC with COPD exhibited a higher proportion of CD8+CD103+TRM compared to NSCLC without COPD (11.9% vs. 4.6%, P = 0.040). CONCLUSIONS: The study identified NSCLC with COPD as a favorable lung cancer type for neoadjuvant immunotherapy, offering a new perspective on the multimodality treatment of this patient population. Down-regulated HHLA2 in NSCLC with COPD might improve the MPR rate to neoadjuvant immunotherapy owing to the enrichment of CD8+CD103+TRM. TRIAL REGISTRATION: Approval for the collection and utilization of clinical samples was granted by the Ethics Committee of Shanghai Pulmonary Hospital (Approval number: K23-228).

HRG inhibits liver cancer lung metastasis by suppressing neutrophil extracellular trap formation.

BACKGROUND: Distant metastasis is a sign of poor prognosis for cancer patients. Extrahepatic liver cancer metastases commonly spread to the lung. Remodelling of the metastatic microenvironment is essential for tumour metastasis. Neutrophil-associated metastatic microenvironment contributes to the early metastatic colonisation of cancer cells in the lung. METHOD: The lung metastasis models were constructed via treated cancer cells by tail vein injection into mice. And samples of lung were harvested at the indicated time to analyze tumor growth and immune cells in the microenvironment. Tumors and lung metastasis specimens were obtained via surgical operations for research purposes. Neutrophils were obtained from peripheral blood of patients with liver cancer or healthy donors (HD). RESULTS: Hepatocellular carcinoma cells reduce the secretion of histidine-rich glycoprotein (HRG), regulate the recruitment and activation of neutrophils in the metastatic microenvironment and promote the production of neutrophil extracellular traps (NETs), thereby promoting liver cancer lung metastasis. HRG binds to FCγR1 on the neutrophil membrane while inhibiting PI3K and NF-κB activation, thereby reducing IL-8 secretion to reduce neutrophil recruitment. Meanwhile, HRG inhibited IL8-MAPK and NF-κB pathway activation and ROS production, resulting in reduced NETs formation. CONCLUSIONS: Our study reveals that liver cancer regulates neutrophil recruitment and NETs formation in the metastatic microenvironment by reducing HRG secretion, thereby promoting tumour lung metastasis. The results of this study will contribute to the development of possible strategies for treating metastases.

MUC1 promotes lung metastases of liver cancer by impairing anti-tumor immunity.

PURPOSE: MUC1 is a membrane bound protein that can regulate tumor progression but its role in tumor metastasis and the metastatic microenvironment remains unclear. METHODS: We performed differential gene analysis for primary liver cancer (n = 31) and lung metastases (n = 31) using the Gene Expression Omnibus (GEO) dataset (GSE141016) and obtained RNA sequencing data from 374 liver cancer and 50 normal tissues from The Cancer Genome Atlas (TCGA). We analyzed the prognostic value of MUC1 and the relationship between MUC1 and the TME using online databases and a clinical cohort. Immunohistochemistry detected MUC1 in normal liver, liver cancer, and lung metastases. Multiplex immunohistochemistry staining detected immune cells in the metastatic microenvironment. RESULTS: High MUC1 expression levels in hepatocellular carcinoma are associated with worse clinical prognosis and higher rates of lung metastasis. In addition, we observed a correlation between MUC1 and multiple immune cells in the metastatic microenvironment. In paired primary liver cancer and lung metastatic tumor tissues from the same patient, we observed higher MUC1 protein levels in lung metastases than in primary liver cancer. Furthermore, MUC1 was negatively correlated with CD8+T and Treg cells in the metastatic tumor microenvironment and positively correlated with DC. In addition, we found that MUC1 was associated with CD8+T cell activation and function using flow cytometry in another cohort of patients with liver cancer. CONCLUSION: These data confirm the potential of MUC1 as a prognostic marker and therapeutic target.

Landscape of immunocytes infiltration and prognostic immune-related genes in hepatocellular carcinoma.

BACKGROUND: /Objective: The therapeutic efficacy and prognosis of patients with hepatocellular carcinoma (HCC) remain unsatisfactory, and further studies are supposed to provide more effective treatment strategies. Immune cells in extracellular matrix play an important role in the therapeutic effect and prognosis of hepatocellular carcinoma. METHOD: To explore the mechanism of immune cells, we analysed the relationship between immune infiltration and gene expression profile through public databases. Patients were divided into high and low groups according to immune score by the ESTIMATE algorithm. It was found that the prognosis and clinical data of patients with liver cancer were correlated with immune scores. RESULTS: Using the CIBERSORT method, we identified 21 types of immunocytes infiltration in HCC and demonstrated that these immune cells have clinical and prognostic implications. According to immune score, 590 differentially expressed genes were identified, and 6 key immune-related genes were screened by univariate COX analysis and lasso regression. In addition, the expression of EGLN3, KLRB1, MSC and HMOX1 was found to be correlated with immune cells (B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages and dendritic cells) in HCC by the TIMER algorithm. CONCLUSIONS: These findings provide new clues to understanding the mechanisms of immune cells in HCC and lay the foundation for the development of new prognostic strategies in HCC.

Prussian Blue Scavenger Ameliorates Hepatic Ischemia-Reperfusion Injury by Inhibiting Inflammation and Reducing Oxidative Stress.

Oxidative stress and excessive inflammatory responses are the two critical mechanisms of hepatic ischemia-reperfusion injury (HIRI) encountered in many clinical settings, including following hepatectomy and liver transplantation. Effective anti-inflammatory and anti-oxidative pharmacological interventions are urgently needed to counter HIRI. The present study showed that a biocompatible Prussian blue (PB) scavenger with reactive oxygen species (ROS) scavenging and anti-inflammatory properties might be used a promising treatment for HIRI. Following intravenous administration, PB scavenger was mainly distributed in the liver, where it showed excellent ability to alleviate apoptosis, tissue injury and organ dysfunction after HIRI. PB scavenger was found to protect liver tissue by scavenging ROS, reducing neutrophil infiltration and promoting macrophage M2 polarization. In addition, PB scavenger significantly reduced oxidative stress in primary hepatocytes, restoring cell viability under oxidative stress condition. PB scavenger effectively reduced lipopolysaccharide-stimulated inflammation in RAW 264.7 cells. These findings indicate that PB scavenger may be a potential therapeutic agent for the treatment of HIRI, providing an alternative treatment for ROS-associated and inflammatory liver diseases.

Aurora kinase A regulates liver regeneration through macrophages polarization and Wnt/ß-catenin signalling.

BACKGROUND AND AIMS: Liver regeneration is a complex process regulated by a variety of cells, cytokines and biological pathways. Aurora kinase A (AURKA) is a serine/threonine kinase that plays a role in centrosome maturation and spindle formation during the cell division cycle. The purpose of this study was to further explore the mechanism of AURKA on liver regeneration and to identify new possible targets for liver regeneration. METHODS: The effect and mechanism of AURKA on liver regeneration were studied using a 70% hepatectomy model. Human liver organoids were used as an in vitro model to investigate the effect of AURKA on hepatocyte proliferation. RESULTS: AURKA inhibition significantly reduced the level of ß-catenin protein by reducing the phosphorylation level of glycogen synthase kinase-3ß (GSK-3ß), leading to the inhibition of liver regeneration. Further studies showed that AURKA co-localized and interacted with GSK-3ß in the cytoplasm of hepatocytes. When phosphorylation of GSK-3ß was enhanced, the total GSK-3ß level remained unchanged, while AURKA was not affected, and ß-catenin protein levels were increased. In addition, AURKA inhibition affected the formation and proliferation of human liver organoids. Furthermore, AURKA inhibition led to the polarization of M1 macrophages and the release of interleukin-6 and Tumour necrosis factor α, which also led to reduced liver regeneration and increased liver injury. CONCLUSIONS: These results provide more details on the mechanism of liver regeneration and suggest that AURKA is an important regulator of this mechanism.

Regeneration and activation of liver progenitor cells in liver cirrhosis.

Cirrhosis is characterized as the progress of regenerative nodules surrounded by fibrous bands in response to chronic hepatic injury and causes portal hypertension and end-stage hepatic disease. Following liver injury, liver progenitor cells (LPCs) can be activated and differentiate into hepatocytes in order to awaken liver regeneration and reach homeostasis. Recent research has uncovered some new sources of LPCs. Here, we update the mechanisms of LPCs-mediated liver regeneration in cirrhosis by introducing the origin of LPCs and LPCs' niche with a discussion of the influence of LPC-related cells. This article analyzes the mechanism of regeneration and activation of LPCs in cirrhosis in recent years aiming to provide help for clinical application.