Priming with LSD1 inhibitors promotes the persistence and antitumor effect of adoptively transferred T cells.

The antitumor efficacy of adoptively transferred T cells is limited by their poor persistence, in part due to exhaustion, but the underlying mechanisms and potential interventions remain underexplored. Here, we show that targeting histone demethylase LSD1 by chemical inhibitors reshapes the epigenome of in vitro activated and expanded CD8+ T cells, and potentiates their antitumor efficacy. Upon T cell receptor activation and IL-2 signaling, a timely and transient inhibition of LSD1 suffices to improve the memory phenotype of mouse CD8+ T cells, associated with a better ability to produce multiple cytokines, resist exhaustion, and persist in both antigen-dependent and -independent manners after adoptive transfer. Consequently, OT1 cells primed with LSD1 inhibitors demonstrate an enhanced antitumor effect in OVA-expressing solid tumor models implanted in female mice, both as a standalone treatment and in combination with PD-1 blockade. Moreover, priming with LSD1 inhibitors promotes polyfunctionality of human CD8+ T cells, and increases the persistence and antitumor efficacy of human CD19-CAR T cells in both leukemia and solid tumor models. Thus, pharmacological inhibition of LSD1 could be exploited to improve adoptive T cell therapy.

Efficacy and surgical safety of sequential surgical resection after pembrolizumab plus chemotherapy for initial unresectable stage IIIB non-small cell lung cancer.

INTRODUCTION: Neoadjuvant immunochemotherapy is effective in resectable NSCLC. However, its role in unresectable stage IIIB NSCLC patients remains controversial. This study aimed to demonstrate the efficacy and safety of neoadjuvant immunochemotherapy followed by surgical resection to treat initial unresectable stage IIIB NSCLC patients. METHODS: This study retrospectively analyzed 59 initial unresectable stage IIIB NSCLC patients who received induction pembrolizumab combined with chemotherapy between June 2019 and April 2022. Clinical characteristics, radiological and pathological responses, and survival outcomes were collected and evaluated. RESULTS: Fifity-nine initial unresectable stage IIIB NSCLC patients were identified and divided into surgery (n = 23) and non-surgery (n = 36) groups with a median follow-up time of 15.0 months. The median PFS/DFS of the surgery group was significantly longer than the non-surgery group (not reached vs. 15.5 months, p = 0.0031). The median overall survival (OS) was not reached in both groups, and the OS rate was 100% (23/23) in the surgery group and 83.3% (30/36) in the non-surgery group. The pathological analysis suggested that 13 of 23 patients (56.5%) achieved major pathological response (MPR) or pathological complete response (pCR), and more squamous cell carcinoma cases were observed in the MPR group compared to the non-MPR group (p = 0.034). All patients in the surgery group had an R0 resection, and no surgical-related mortality was recorded; only three patients (13.0%) experienced any postoperative complications. CONCLUSION: In this retrospective study, surgical resection after neoadjuvant immunochemotherapy was promising for initial unresectable stage IIIB NSCLC patients, with a high MPR rate and good surgical safety.

EZH2 inhibition activates dsRNA-interferon axis stress and promotes response to PD-1 checkpoint blockade in NSCLC.

Lung cancer is the leading cause of cancer death and immunotherapy had been approved be a useful approach for NSCLC therapy. However, only part of the patients responds to checkpoint inhibitors. The EZH2, as a histone modification regulator, is overexpressed in NSCLC and negatively regulates the interferon-stimulated genes. Here, we demonstrate that EZH2 inhibition increases the double-strand RNA (dsRNA) level and then triggers the IFN pathway stress which is dependent on the pattern recognition receptors (TLR3, MDA5). The antigen presentation genes and PDL1 were also upregulated by inhibition of EZH2. Furthermore, in the immunocompetent LLC tumor model, the inhibition of EZH2 causes tumor regression and enhances the CD8+T cell infiltration. The EZH2 depletion triggers significant responses of the LLC mouse model to anti-PD1 therapy. This study identifies that inhibition of EZH2 promotes the dsRNA interferon driven antitumor immunity and enhances the anti-PD1 antitumor efficacy in NSCLC. These data suggest that EZH2 inhibition combined with anti-PD1/PDL1 is a promising lung cancer treatment strategy.

Gremlin2 Activates Fibroblasts to Promote Pulmonary Fibrosis Through the Bone Morphogenic Protein Pathway.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing unremitting extracellular matrix deposition. Transforming growth factor-ß (TGF-ß) superfamily involves bone morphogenetic proteins (BMPs) and TGF-ß, and the balance between the activation of TGF-ß-dependent SMADs (Smad2/3) and BMP-dependent SMADs (Smad1/5/8) is essential for fibrosis process. GREM2, initially identified as a TGF-ß-inducible gene, encodes a small secreted glycoprotein belonging to a group of matricellular proteins, its role in lung fibrosis is not clear. Here, we identified Gremlin2 as a key regulator of fibroblast activation. Gremlin2 was highly expressed in the serum and lung tissues in IPF patients. Bleomycin-induced lung fibrosis model exhibited high expression of Gremlin2 in the bronchoalveolar lavage fluid (BALF) and lung tissue. Isolation of primary cells from bleomycin-induced fibrosis lung showed a good correlation of Gremlin2 and Acta2 (α-SMA) expressions. Overexpression of Gremlin2 in human fetal lung fibroblast 1 (HFL-1) cells increased its invasion and migration. Furthermore, Gremlin2 regulates fibrosis functions through mediating TGF-ß/BMP signaling, in which Gremlin2 may activate TGF-ß signaling and inhibit BMP signaling. Therefore, we provided in vivo and in vitro evidence to demonstrate that Gremlin2 may be a potential therapeutic target for the treatment of IPF.

Loss of LIMCH1 predicts poor prognosis in patients with surgically resected Lung Adenocarcinoma: A study based on Immunohistochemical Analysis and Bioinformatics.

Background: LIMCH1, a novel actin-binding protein, is reported to correlate with tumorigenesis in multiple cancer types, but its clinical prognostic value in lung adenocarcinoma (LUAD) patients remains unclear. Methods: A total of 196 patients with LUAD who underwent R0 resection were included for analysis. We integrated immunohistochemistry (IHC) and data mining analyses to determine LIMCH1 expression in tumor specimens; the chi-square test was used to explore the correlation between clinicopathologic factors and LIMCH1 expression in LUAD; Kaplan-Meier curves and the Cox proportional hazards model were used to investigate the clinical prognostic role of LIMCH1 expression in patients with LUAD; and DAVID enrichment and gene set enrichment analysis (GSEA) were used to determine the underlying molecular mechanism. Results: LIMCH1 protein and mRNA expressions were significantly decreased in LUAD tissues. LIMCH1 mRNA expression was a potential diagnostic indicator in the TCGA cohort, and was associated with poor prognosis. IHC results in our LUAD cohort demonstrated that the LIMCH1 expression level was significantly associated with pleural invasion, tumor length, tumor differentiation grade, and clinical tumor stage. Patients with higher LIMCH1 expression had longer overall survival times. Cox multivariate survival analysis showed that LIMCH1 expression independently predicted the outcome. GO and KEGG clustering analyses showed that LIMCH1-related genes may be involved in 'cell adhesion', 'signal transduction', and several cancer-related pathways. GSEA showed 8 enriched hallmarks in the low LIMCH1 expression group, including mTOR signaling, MYC signaling, DNA repair, and G2M checkpoint. Conclusions: Our findings suggest that LIMCH1 may serve as a promising biomarker to predict LUAD prognosis.

Overexpression of KIAA0101 Promotes the Progression of Non-small Cell Lung Cancer.

Lung cancer is the leading cause of cancer related death worldwide, with a continue-rising incidence. The proliferating cell nuclear antigen binding protein KIAA0101 is highly expressed in various types of cancer, including non-small cell lung cancer (NSCLC). However, its biological role and underlying mechanisms in NSCLC remains unclear. We downloaded KIAA0101 mRNA and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and verified the KIAA0101 expression by conducting experiments of immunochemistry (IHC), immunofluorescence (IF), quantitative real-time PCR (qRT-PCR) and western-blot. Functional experiments were performed to explore the biological roles in vitro and in vivo. The results showed that KIAA0101 was overexpressed in NSCLC tissues and cell lines. High KIAA0101 expression was associated with high T stage, nodal invasion, advanced tumor stage, and poor overall survival (P<0.01). The receiver operating characteristic (ROC) curves showed that KIAA0101 could distinguish NSCLC from paired normal tissues with statistical significance (AUC=0.969, P<0.001). The multivariate analysis revealed that KIAA0101 was an independent prognostic factor for overall survival (HR=1.249, 95% CI: 1.001-1.559, P=0.049). Furthermore, KIAA0101 knockdown induced G1 phase cell cycle arrest and inhibited NSCLC cell proliferation and migration. We also found that the depletion of KIAA0101 decreased tumor volume in nude mice. In summary, our findings suggested that KIAA0101 was a reliable diagnostic and prognostic factor in NSCLC, with potential to be a promising treatment target.