Tumor-associated macrophage enhances PD-L1-mediated immune escape of bladder cancer through PKM2 dimer-STAT3 complex nuclear translocation.

Tumor-associated macrophages (TAMs) are important components of the tumor microenvironment (TME) and strongly associated with poor prognosis and drug resistance, including checkpoint blockade immunotherapy in solid tumor patients. However, the mechanism by which TAM affects immune metabolism reprogramming and immune checkpoint signalling pathway in the TME remains elusive. In this study we found that transforming growth factor-beta (TGF-ß) secreted by M2-TAMs increased the level of glycolysis in bladder cancer (BLCA) and played important role in PD-L1-mediated immune evasion through pyruvate kinase isoenzymes M2 (PKM2). Mechanistically, TGF-ß promoted high expression of PKM2 by promoting the nuclear translocation of PKM2 dimer in conjunction with phosphorylated signal transducer and activator of transcription (p-STAT3), which then exerted its kinase activity to promote PD-L1 expression in BLCA. Moreover, SB-431542 (TGF-ß blocker) and shikonin (PKM2 inhibitor) significantly reduced PD-L1 expression and inhibited BLCA growth and organoids by enhancing anti-tumor immune responses. In conclusion, M2-TAM-derived TGF-ß promotes PD-L1-mediated immune evasion in BLCA by increasing the PKM2 dimer-STAT3 complex nuclear translocation. Combined blockade of the TGF-ß receptor and inhibition of PKM2 effectively prevent BLCA progression and immunosuppression, providing a potential targeted therapeutic strategy for BLCA.

Stable PbS colloidal quantum dot inks enable blade-coating infrared solar cells.

Infrared solar cells are more effective than normal bandgap solar cells at reducing the spectral loss in the near-infrared region, thus also at broadening the absorption spectra and improving power conversion efficiency. PbS colloidal quantum dots (QDs) with tunable bandgap are ideal infrared photovoltaic materials. However, QD solar cell production suffers from small-area-based spin-coating fabrication methods and unstable QD ink. Herein, the QD ink stability mechanism was fully investigated according to Lewis acid-base theory and colloid stability theory. We further studied a mixed solvent system using dimethylformamide and butylamine, compatible with the scalable manufacture of method-blade coating. Based on the ink system, 100 cm2 of uniform and dense near-infrared PbS QDs (~ 0.96 eV) film was successfully prepared by blade coating. The average efficiencies of above absorber-based devices reached 11.14% under AM1.5G illumination, and the 800 nm-filtered efficiency achieved 4.28%. Both were the top values among blade coating method based devices. The newly developed ink showed excellent stability, and the device performance based on the ink stored for 7 h was similar to that of fresh ink. The matched solvent system for stable PbS QD ink represents a crucial step toward large area blade coating photoelectric devices.

A feed-forward loop based on aerobic glycolysis and TGF-ß between tumor-associated macrophages and bladder cancer cells promoted malignant progression and immune escape.

PURPOSE: Immunotherapy with programmed cell death 1/ligand 1 (PD-1/PD-L1) checkpoint inhibitors has revolutionized the systemic treatment of solid tumors, including bladder cancer. Previous studies have shown that enhanced glycolysis, tumor-associated macrophage (TAM) infiltration, and TGF-ß secretion in the tumor microenvironment (TME) are closely related to PD-1/PD-L1 inhibitor immunotherapy resistance. However, the potential mechanism of their interaction in bladder cancer has not been fully uncovered. METHODS: By coculturing bladder cancer cells and TAMs, we studied the relationship and interaction mechanism between tumor cell glycolysis, TAM functional remodeling, TGF-ß positive feedback secretion, and PD-L1 mRNA m6A methylation in the bladder cancer microenvironment. RESULTS: Bioinformatics analysis and IHC staining found a close correlation between tumor glycolysis, M2 TAM infiltration, and the prognosis of bladder cancer patients. In Vitro experiments demonstrated that bladder cancer cells could re-educate M2 TAMs through lactate and promote TGF-ß secretion via the HIF-1α signaling pathway. Reciprocally, in vitro, and in vivo experiments validated that M2 TAMs could promote glycolysis in bladder cancer cells by TGF-ß via the Smad2/3 signaling pathways. Furthermore, M2 TAMs could also promote CSCs and EMT of bladder cancer cells. More importantly, we found M2 TAMs enhance PD-L1 mRNA m6A methylation by promoting METLL3 expression in bladder cancer via the TGF-ß/Smad2/3 pathway in the TME. CONCLUSIONS: Our study highlights a feed-forward loop based on aerobic glycolysis and TGF-ß between M2 TAMs and bladder cancer cells, which may be a potential mechanism of malignant progression and immunotherapy resistance in bladder cancer.

High expression of COL6A1 predicts poor prognosis and response to immunotherapy in bladder cancer.

Extracellular matrix (ECM), as an important framework for tumor microenvironment, plays important roles in many critical processes, including tumor growth, invasion, immune suppression, and drug resistance. However, few biomarkers of ECM-related genes (ERGs) have been developed for prognosis prediction and clinical treatment of bladder cancer (BC) patients. Bioinformatics analysis and LC-MS/MS analysis were used to screen differentially expressed ERGs in BC. Multivariate Cox regression analysis and Lasso regression analysis were used to construct and validate an ERGs-based prognostic prediction model for BC. Immunohistochemistry was used to detect the protein expression of hub gene-COL6A1 in BC patients. Using bioinformatics analysis from The Cancer Genome Atlas (TCGA) database and proteomic analysis from our BC cohort, we constructed and validated an effective prognostic prediction model for BC patients based on four differentially expressed ERGs (MAP1B, FBN1, COL6A1, and MFAP5). Moreover, we identified human collagen VI-COL6A1 was a hub gene in this prognostic prediction model and found that COL6A1 was closely related to malignancy progression, prognosis, and response to PD-1 inhibitor immunotherapy in BC. Our findings highlight the satisfactory predictive value of ECM-related prognostic models in BC and suggested that COL6A1 may be a potential biomarker in predicting malignant progression, prognosis, and efficacy of immunotherapy in BC.

High expression of GMNN predicts malignant progression and poor prognosis in ACC.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine neoplasm, which is characterized by poor prognosis and high recurrence rate. Novel and reliable prognostic and metastatic biomarkers are lacking for ACC patients. This study aims at screening potential prognostic biomarkers and therapeutic targets of ACC through bioinformatic methods and immunohistochemical (IHC) analysis. METHODS: In the present study, by using the Gene Expression Omnibus (GEO) database we identified differentially expressed genes (DEGs) in ACC and validated these DEGs in The Cancer Genome Atlas (TCGA) ACC cohort. A DEGs-based signature was additionally constructed and we assessed its prognosis and prescient worth for ACC by survival analysis and nomogram. Immunohistochemistry (IHC) was used to verify the relationship between hub gene-GMNN expressions and clinicopathologic outcomes in ACC patients. RESULTS: A total of 24 DEGs correlated with the prognosis of ACC were screened from the TCGA and GEO databases. Five DEGs were subsequently selected in a signature which was closely related to the survival rates of ACC patients and GMNN was identified as the core gene in this signature. Univariate and multivariate Cox regression showed that the GMNN was an independent prognostic factor for ACC patients (P < 0.05). Meanwhile, GMNN was closely related to the OS and PFI of ACC patients treated with mitotane (P < 0.001). IHC confirmed that GMNN protein was overexpressed in ACC tissues compared with normal adrenal tissues and significantly correlated with stage (P = 0.011), metastasis (P = 0.028) and Ki-67 index (P = 0.014). CONCLUSIONS: GMNN is a novel tumor marker for predicting the malignant progression, metastasis and prognosis of ACC, and may be a potential therapeutic target for ACC.

Efficient Near-Infrared PbS Quantum Dot Solar Cells Employing Hydrogenated In2 O3 Transparent Electrode.

Infrared solar cells are regarded as candidates for expanding the solar spectrum of c-Si cells, and the window electrodes are usually transparent conductive oxide (TCO) such as widely used indium tin oxide material. However, due to the low transmittance of the TCO in the near-infrared region, most near-infrared light cannot penetrate the electrode and be absorbed by the active layer. Here, the propose a simple procedure to fabricate the window materials with high near-infrared transmittance and high electrical conductivity, namely the hydrogen-doped indium oxide (IHO) films prepared by room temperature magnetron sputtering. The low-temperature annealed IHO conductive electrodes exhibit high mobility of 98 cm2 V-1 s-1 and high infrared transmittance of 85.2% at 1300 nm, which endows the lead quantum dot infrared solar cell with an improved short-circuit current density of 37.2 mA cm-2 and external quantum efficiency of 70.22% at 1280 nm. The proposed preparation process is simple and compatible with existing production lines, which gifts the IHO transparent conductive film great potential in broad applications that simultaneously require high infrared transmittance and high conductivity.

Matching Charge Extraction Contact for Infrared PbS Colloidal Quantum Dot Solar Cells.

Infrared solar cells (IRSCs) can supplement silicon or perovskite SCs to broaden the utilization of the solar spectrum. As an ideal infrared photovoltaic material, PbS colloidal quantum dots (CQDs) with tunable bandgaps can make good use of solar energy, especially the infrared region. However, as the QD size increases, the energy level shrinking and surface facet evolution makes us reconsider the matching charge extraction contacts and the QD passivation strategy. Herein, different to the traditional sol-gel ZnO layer, energy-level aligned ZnO thin film from a magnetron sputtering method is adopted for electron extraction. In addition, a modified hybrid ligand recipe is developed for the facet passivation of large size QDs. As a result, the champion IRSC delivers an open circuit voltage of 0.49 V and a power conversion efficiency (PCE) of 10.47% under AM1.5 full-spectrum illumination, and the certified PCE is over 10%. Especially the 1100 nm filtered efficiency achieves 1.23%. The obtained devices also show high storage stability. The present matched electron extraction and QD passivation strategies are expected to highly booster the IR conversion yield and promote the fast development of new conception QD optoelectronics.