A novel chemical, STF-083010, reverses tamoxifen-related drug resistance in breast cancer by inhibiting IRE1/XBP1

Background: As the indication for immunotherapy is rapidly expanding, it is crucial to accurately identify patients who are likely to respond. Infiltration of B cells into many tumor types correlates with a good response to immune checkpoint inhibitor (ICI) therapy. However, B cells’ roles in the anti-tumor response are far from clear.Methods: Based on single-cell transcriptomic data for ICI-treated patients, we identified a B-cell cluster [B_IR (ICI-Responsive B) cells] and described the phenotype, cell–cell communication, biological processes, gene signature, and prognosis value of B_IR cells through bioinformatic analysis, tissue immunofluorescence, and animal experiments. Surgery samples from 12 non-small cell lung carcinoma (NSCLC) patients with adjuvant checkpoint blockade were evaluated as external validation.Results: B_IR cells were identified as a subset of CD20⁺CD22⁺ADAM28⁺ B cells with a memory phenotype. Bioinformatic analysis revealed that B_IR cells had enhanced cell viability and epigenetic regulation, and that ALOX5AP, MIF, and PTPRC/CD45 expressed by myeloid cells may be critical coordinators of diverse biological processes of B_IR cells. Immunofluorescence confirmed the presence of B_IR cells in tertiary lymphoid structures (TLSs) in skin SCC, RCC, CRC, and breast cancer. B_IR-associated gene signatures correlate with positive outcomes in patients with melanoma, glioblastoma, NSCLC, HNSCC, or RCC treated with ICI therapy, and B_IR-cell density predicted NSCLC patients’ response to checkpoint immunotherapy. In line with this, melanoma-bearing mice depleted of B_IR cells were resistant to ICIs.Conclusions: CD20⁺CD22⁺ADAM28⁺ B_IR cells were present in cancer-associated TLS and promoted the response to ICI therapy.

Background Hormones are identified as key biological variables in tumor immunity. However, previous researches mainly focused on the immune effect of steroid hormones, while the roles that thyroid-stimulating hormone (TSH) played in the antitumor response were far from clear. Methods The source of TSH was determined using single-cell transcriptomic, histologic, quantitative PCR, and ELISA analysis. The influence of TSH on tumor proliferation, invasion, and immune evasion was evaluated in multiple cell lines of thyroid cancer, glioma, and breast cancer. Then transcriptomic sequencing and cellular experiments were used to identify signaling pathways. TSH receptor (TSHR) inhibitor was injected into homograft mouse tumor models with or without anti-programmed cell death protein-1 antibody. Results Monocyte-derived dendritic cells (moDCs) highly expressed TSHα and TSHβ2 and were the primary source of TSH in the tumor microenvironment. TSH released by moDCs promoted proliferation and invasion of tumors with high TSHR expressions, such as thyroid cancers and glioma. TSH also induced tumor programmed death-ligand 1 (PD-L1) expression through the TSHR-AC-PKA-JNK-c-JUN pathway. TSHR inhibitors reversed tumor immune evasion by inhibiting PD-L1 expression in tumor and myeloid cells and enhancing Teff activation. Conclusions TSH–TSHR axis promotes tumor evasion in thyroid cancers and glioma. TSH suppression therapy is an effective therapeutic strategy for combination in immune checkpoint blockades.

Thyroid nodules can be classified into benign and malignant tumors. However, distinguishing between these two types of tumors can be challenging in clinics. Since malignant nodules require surgical intervention whereas asymptomatic benign tumors do not, there is an urgent need for new techniques that enable accurate diagnosis of malignant thyroid nodules. Here, we used ¹H NMR spectroscopy coupled with pattern recognition techniques to analyze the metabonomes of thyroid tissues and their extracts from thyroid lesion patients (n = 53) and their adjacent healthy thyroid tissues (n = 46). We also measured fatty acid compositions using GC−FID/MS techniques as complementary information. We demonstrate that thyroid lesion tissues can be clearly distinguishable from healthy tissues and malignant tumors can also be distinguished from the benign tumors based on the metabolic profiles, both with high sensitivity and specificity. In addition, we show that thyroid lesions are accompanied with disturbances of multiple metabolic pathways, including alterations in energy metabolism (glycolysis, lipid and TCA cycle), promotions in protein turnover, nucleotide biosynthesis as well as phosphatidylcholine biosynthesis. These findings provide essential information on the metabolic features of thyroid lesions and demonstrate that metabonomics technology can be potentially useful in the rapid and accurate preoperative diagnosis of malignant thyroid nodules.

Thousands of lncRNAs have been identified but few have been functionally characterized in triple negative breast cancer (TNBC). LINC00152 was known as cytoskeleton regulator RNA (CYTOR) and expressed in various cancers including breast cancer. But the underlying molecular mechanism of LINC00152 in pathogenesis of TNBC have not been elucidated. In our study, we identified that LINC00152 expression was dramatically elevated in TNBC tissue and cells. Inhibition or overexpression of LINC00152 obviously increased or suppressed PTEN protein expression but did not affect the mRNA expression level. Our further experiments showed up-regulated LINC00152 in TNBC obviously enhanced NEDD4-1 mediated ubiquitination and degradation of PTEN protein. Finally, we demonstrated that YY1 bound with LINC00152 promotor and mostly inhibited the transcription of LINC00152. Furthermore, analysis of clinical samples resource retrieved from databases suggested high LINC00152 expression was correlated with ER or PR negative expression, late TNM stage and lymphatic invasion, as well as shorter overall survival time in patients. Consequently, this study firstly reveals that up-regulated LINC00152 mediates PTEN protein stability attenuation in TNBC.

Whether sonography is an appropriate imaging modality for cervical lymph nodes in patients with papillary thyroid microcarcinoma (PTMC) remains unclear. Hence, this study aimed to evaluate the diagnostic value of ultrasonography (US) features for lymph node metastasis in PTMC. Seven hundred twelve patients with PTMC who underwent conventional ultrasonography examinations of the cervical lymph nodes were included. All included cases underwent total thyroidectomy plus prophylactic central lymph node dissection. The included lymph nodes were marked superficially, and the corresponding lymph nodes were completely removed and sent for pathological examination. The US features of lymph nodes with and without metastasis were compared, and the odds ratios of the suspicious US features were determined with univariate and multivariate analyses. Round shape, loss of an echogenic fatty hilum, cystic change, calcification, and abnormal vascularity were significantly more common in metastatic than nonmetastatic lymph nodes, whereas the boundary and echo did not significantly differ. Multivariate logistic regression analysis showed that round shape, loss of echogenic fatty hilum, cystic change, calcification, and abnormal vascularity were independent predictive factors for the assessment of metastatic lymph nodes. Round shape had the highest sensitivity of all variables, while loss of an echogenic fatty hilum had the highest specificity and accuracy. The area under the receiver operating characteristic curve, which was calculated to verify the relationship between the various US features and metastatic lymph nodes, was 0.793. Our study found that the US features of round shape, cystic change, calcification, loss of echogenic fatty hilum, and abnormal vascularity were useful sonographic criteria for differentiating between cervical lymph nodes with and without metastasis.