Corrigendum: ITGAL expression in non-small-cell lung cancer tissue and its association with immune infiltrates.

[This corrects the article DOI: 10.3389/fimmu.2024.1382231.].

ITGAL expression in non-small-cell lung cancer tissue and its association with immune infiltrates.

Background: Integrin subunit alpha L (ITGAL) encodes an integrin component of LFA-1 and is a membrane receptor molecule widely expressed on leukocytes. It plays a key role in the interaction between white blood cells and other cells. There was a significant correlation between the expression of ITGAL and the tumor microenvironment in a number of cancers. However, experimental studies targeting ITGAL and immune cell infiltration in non-small-cell lung cancer (NSCLC) and the response to immune checkpoint inhibitor therapy are lacking. Methods: Data were obtained from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases to explore the relationship between ITGAL expression and prognosis, as well as the immune cell infiltration in patients with NSCLC. In addition, immunohistochemical staining for ITGAL and multiplex immunofluorescence (mIF) staining for ITGAL, CD20, CD68, CD4, and CD8 from tissue microarrays containing 118 tumor tissues and paired paracancerous tissues from patients with NSCLC were performed. The correlation between ITGAL expression and clinical factors, as well as the immunophenotypes of tumor-infiltrating immune cells, were also analyzed. Results: In NSCLC tumor tissues, ITGAL was downregulated compared with matched paracancerous tissues, and low ITGAL expression was associated with a poor prognosis of NSCLC patients. Subsequently, immunohistochemistry results for tissue microarray showed that ITGAL expression was mainly elevated in tumor stroma and areas with highly infiltrated immune cells. ITGAL expression was higher in paracancerous tissues than tumor tissues. Furthermore, mIF results indicated that the patients with ITGAL-high expression tend had significantly higher CD8+ T cells, CD68+ macrophages, CD4+ T cells, and CD20+ B cells infiltration in their tumor tissues. Immunophenotypes were classified into three categories, that is deserted, excluded, and inflamed types, according to each kind of immune cell distribution in or around the cancer cell nest. MIF results showed that ITGAL expression level was correlated with the immunophenotypes. Furthermore, ITGAL expression was associated with the prognosis of NSCLC in patients with immune checkpoint inhibitor therapy and the patients with high ITGAL expression tends have better outcomes. Conclusions: ITGAL may be used as a biomarker for assessing the immune microenvironment in patients with NSCLC.

SOD2 promotes the immunosuppressive function of mesenchymal stem cells at the expense of adipocyte differentiation.

The potent immunomodulatory function of mesenchymal stem/stromal cells (MSCs) elicited by proinflammatory cytokines IFN-γ and TNF-α (IT) is critical to resolve inflammation and promote tissue repair. However, little is known about how the immunomodulatory capability of MSCs is related to their differentiation competency in the inflammatory microenvironment. In this study, we demonstrate that the adipocyte differentiation and immunomodulatory function of human adipose tissue-derived MSCs (MSC(AD)s) are mutually exclusive. Mitochondrial reactive oxygen species (mtROS), which promote adipocyte differentiation, were decreased in MSC(AD)s due to IT-induced upregulation of superoxide dismutase 2 (SOD2). Furthermore, knockdown of SOD2 led to enhanced adipogenic differentiation but reduced immunosuppression capability of MSC(AD)s. Interestingly, the adipogenic differentiation was associated with increased mitochondrial biogenesis and upregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A/PGC-1α) expression. IT inhibited PGC-1α expression and decreased mitochondrial mass but promoted glycolysis in an SOD2-dependent manner. MSC(AD)s lacking SOD2 were compromised in their therapeutic efficacy in DSS-induced colitis in mice. Taken together, these findings indicate that the adipogenic differentiation and immunomodulation of MSC(AD)s may compete for resources in fulfilling the respective biosynthetic needs. Blocking of adipogenic differentiation by mitochondrial antioxidant may represent a novel strategy to enhance the immunosuppressive activity of MSCs in the inflammatory microenvironment.

Protective Effect of Electroacupuncture on the Barrier Function of Intestinal Injury in Endotoxemia through HO-1/PINK1 Pathway-Mediated Mitochondrial Dynamics Regulation.

Background and Aims: Endotoxemia (ET) is a common critical illness in patients receiving intensive care and is associated with high mortality and prolonged hospital stay. The intestinal epithelial cell dysfunction is regarded as the "engine" of deteriorated ET. Although electroacupuncture (EA) can mitigate endotoxin-induced intestinal epithelial cell dysfunction in ET, the mechanism through which EA improves endotoxin-induced intestinal injury for preventing ET deterioration needs further investigation. Methods: An in vivo ET model was developed by injecting lipopolysaccharide (LPS) in wild-type and PINK1-knockout mice. An in vitro model was also established by incubating epithelial cells in the serum samples obtained from both groups of mice. Hemin and zinc protoporphyrin IX (ZnPP) were applied to activate or inhibit heme oxygenase 1 (HO-1) production. EA treatment was performed for 30 min consecutively for 5 days before LPS injection, and on the day of the experiment, EA was performed throughout the process. Samples were harvested at 6 h after LPS induction for analyzing tissue injury, oxidative stress, ATP production, activity of diamine oxidase (DAO), and changes in the levels of HO-1, PTEN-induced putative kinase 1 (PINK1), mitochondrial fusion and fission marker gene, caspase-1, and interleukin 1 beta (IL-1ß). Results: In the wild-type models (both in vivo and vitro), EA alleviated LPS-induced intestinal injury and mitochondrial dysfunction, as indicated by decreased reactive oxygen species (ROS) production and oxygen consumption rate (OCR) and reduced levels of mitochondrial fission proteins. EA treatment also boosted histopathological morphology, ATP levels, DAO activity, and levels of mitochondrial fusion proteins in vivo and vitro. The effect of EA was enhanced by hemin but suppressed by Znpp. However, EA + AP, Znpp, or hemin had no effects on the LPS-induced, PINK1-knocked out mouse models. Conclusion: EA may improve the HO-1/PINK1 pathway-mediated mitochondrial dynamic balance to protect the intestinal barrier in patients with ET.

Autophagic Flux Unleashes GATA4-NF-κB Axis to Promote Antioxidant Defense-Dependent Survival of Colorectal Cancer Cells under Chronic Acidosis.

Solid tumors are usually associated with extracellular acidosis due to their increased dependence on glycolysis and poor vascularization. Cancer cells gradually become adapted to acidic microenvironment and even acquire increased aggressiveness. They are resistant to apoptosis but exhibit increased autophagy that is essential for their survival. We here show that NF-κB, a master regulator of cellular responses to stress, is upregulated in colorectal cancer cells adapted to acidosis (CRC-AA). NF-κB is more relied upon for survival in CRC-AA than in their parental cells and drives a robust antioxidant response. Supplementation of antioxidant abolishes the increased sensitivity of CRC-AA to NF-κB inhibition or depletion, suggesting that NF-κB supports the survival of CRC-AA by maintaining redox homeostasis. Because SQSTM1/p62 is known to mediate the selective autophagy of GATA4 that augments NF-κB function, we tested whether the enhanced autophagic flux and consequently the reduction of SQSTM1/p62 in CRC-AA cells could activate the GATA4-NF-κB axis. Indeed, GATA4 is upregulated in CRC-AA cells and augments the NF-κB activity that underlies the increased expression of cytokines, inhibition of apoptosis, and reduction of reactive oxygen species. Interestingly, secretory factors derived from HCT15-AA cells, the soluble ICAM-1 in particular, also possess antioxidant cytoprotective effect against acidic stress. Together, our results demonstrate a prosurvival role of the p62-restricted GATA4-NF-κB axis in cancer cells adapted to acidic microenvironment.

Histone demethylase KDM7A is required for stem cell maintenance and apoptosis inhibition in breast cancer.

Histone demethylase KDM7A regulates neuronal differentiation and development in mammals. In this study, we found that KDM7A was also required for breast cancer stem cells (BCSCs) maintenance. Silencing KDM7A significantly reduced the BCSCs population and mamosphere formation in vitro, and inhibited breast tumor growth in vivo. Restoring KDM7A expression rescued the defect in stem cell maintenance. Our mechanism analysis suggested that KDM7A upregulated the stemness-associated factors KLF4 and c-MYC for BCSCs maintenance. In addition, KDM7A knockdown promoted apoptosis through decreasing BCL2 expression and BAD phosphorylation in breast cancer (BrCa). Furthermore, restoring KDM7A and BCL2 expression rescued apoptosis inhibition in breast cancer, suggesting that KDM7A inhibited apoptosis by upregulating the BCL2 level in breast cancer. In conclusion, KDM7A promotes cancer stem cell maintenance and apoptosis inhibition in breast cancer.

Histone demethylase KDM2B promotes triple negative breast cancer proliferation by suppressing p15INK4B, p16INK4A, and p57KIP2 transcription.

H3K4me3 and H3K36me2 histone demethylase KDM2B is an epigenetic regulatory factor involved in cell proliferation in numerous cells including breast cancer cells, however, the regulatory mechanism of KDM2B in cell proliferation of breast cancer cells, specifically in triple negative breast cancer (TNBC), remains largely unknown. In this study, we showed that higher expression level of KDM2B was associated with poor prognosis in TNBC. Using cell proliferation assay, we found that KDM2B promoted TNBC cell proliferation by suppressing the transcription of the cell cycle inhibitors p15INK4B, p16INK4A, and p57KIP2. Chromatin immunoprecipitation assay results showed that KDM2B bound to the promoters of these genes and thereby reduced the H3K4me3 and H3K36me2 levels, leading to the suppression of gene transcription in a histone demethylation activity-dependent manner. Silencing of p15INK4B, p16INK4A, and p57KIP2 in TNBC cells was shown to restore the promoting effect of KDM2B on TNBC cell proliferation. The present study reveals a novel cell regulatory mechanism through which KDM2B promotes TNBC cell proliferation by binding to the promoters of p15INK4B, p16INK4A, and p57KIP2, which reduces H3K4me3 and H3K36me2 levels to suppress gene transcription.