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Background: Although the lactate pathway has been reported to lead to immune escape through the inhibition of effector T cells, the cancer-intrinsic lactate signature has not been identified, and the immunotherapeutic efficacy and potential mechanism of the lactate signature are still unclear. Methods: We defined a pan-cancer up-lactate score by comparing malignant tissues and normal tissues in the TCGA cohort. The immunotherapeutic efficacy was evaluated in non-small cell lung cancer (NSCLC), metastatic renal cancer (mRCC), bladder cancer (BLCA) and melanoma cohorts. The cancer cell-intrinsic mechanism to immune checkpoint inhibitors (ICIs) resistance was measured using single cell sequencing (scRNA-seq) data. Pathway activation was evaluated in the TCGA cohort and CPTAC cohort with transcriptomics and proteomics. The co-occurrence of up-lactate signature and mTOR signaling was determined by spatial transcriptomics of the tissue samples. Immunotherapy resistance and pathway regulation were validated in the in-house NSCLC cohort. Results: Patients with the high up-lactate scores had significantly short overall survival (OS) than those with the low up-lactate scores (p

Summary: Tumor microenvironment (TME) plays a crucial role in predicting prognosis and response to therapy in lung cancer. Our study established a prognostic and immunotherapeutic predictive model, the tumor immune cell score (TICS), by differentiating cell origins in lung adenocarcinoma (LUAD) based on the transcriptomic data of 2,510 patients in 14 independent cohorts, including 12 public datasets and two in-house cohorts. The high TICS was associated with prolonged overall survival (OS), especially in the early-stage LUAD. For the advanced-stage LUAD, high TICS predicted a superior OS in patients who were treated with immunotherapy instead of chemotherapy or TKI. The result suggested that TICS could serve as an indicator for the prognostic stratification management of patients in the early-stage LUAD, and as a potential guide for therapeutic decision-marking in the advanced-stage LUAD. Our findings provided an insight into prognosis stratification and potential guidance for treatment strategy selection.

Flowering is one of the important defining features of angiosperms. The initiation of flower development and the formation of different floral organs are the results of the interplays among numerous genes. But until now, just fewer genes have been found linked with flower development. And the functions of lots of genes of Arabidopsis thaliana are still unknown. Although, the quartet model successfully simplified the ABCDE model to elaborate the molecular mechanism by introducing protein-protein interactions (PPIs). We still don't know much about several important aspects of flower development. So we need to discriminate even more genes involving in the flower development. In this study, we identified seven differentially modules through integrating the weighted gene co-expression network analysis (WGCNA) and Support Vector Machine (SVM) method to analyze co-expression network and PPIs using the public floral and non-floral expression profiles data of Arabidopsis thaliana. Gene set enrichment analysis was used for the functional annotation of the related genes, and some of the hub genes were identified in each module. The potential floral organ morphogenesis genes of two significant modules were integrated with PPI information in order to detail the inherent regulation mechanisms. Finally, the functions of the floral patterning genes were elucidated by combining the PPI and evolutionary information. It was indicated that the sub-networks or complexes, rather than the genes, were the regulation unit of flower development. We found that the most possible potential new genes underlining the floral pattern formation in A. thaliana were FY, CBL2, ZFN3, and AT1G77370; among them, FY, CBL2 acted as an upstream regulator of AP2; ZFN3 activated the flower primordial determining gene AP1 and AP2 by HY5/HYH gene via photo induction possibly. And AT1G77370 exhibited similar function in floral morphogenesis, same as ELF3. It possibly formed a complex between RFC3 and RPS15 in cytoplasm, which regulated TSO1 and CPSF160 in the nucleus, to control the floral organ morphogenesis. This process might also be fine tuning by AT5G53360 in the nucleus. [ABSTRACT FROM AUTHOR]