Journal Article

TUBA1C orchestrates the immunosuppressive tumor microenvironment and resistance to immune checkpoint blockade in clear cell renal cell carcinoma

Chen, Meixue, Tong, Ming, Li, Junyi, Cao, Qingfei

2024

Overview

Clear cell renal cell carcinoma (ccRCC) poses substantial treatment challenges, especially in advanced stages where the efficacy of immune checkpoint blockade (ICB) therapy varies significantly. Elevated expression of the oncogene has been correlated with poor prognosis in various cancers, however, its role in ccRCC is unclear, especially concerning ICB resistance. Single-cell analysis was used to examine gene expression variations in malignant cells post-ICB therapy. This included investigating TUBA1C expression across different ICB response groups and its relationship with CD274. A general module of action was identified through pan-cancer and pan-tissue analysis. TUBA1C expression and its association with clinical characteristics and prognosis was further validated. Multiple algorithms were employed to explore immune cell infiltration levels, and the DepMap database was utilized to assess gene dependency and mutation status in kidney cancer cell lines. The knockout of TUBA1C was performed using deep learning model, complemented by immunohistochemical assays, clinical cohort and functional assays validations. TUBA1C expression is elevated in malignant cells following ICB therapy and is correlated with ICB resistance in ccRCC. High TUBA1C expression activates PI3K/AKT pathway and is associated with increased infiltration of regulatory T cells and myeloid-derived suppressor cells, which contributes to an immunosuppressive microenvironment in ccRCC. Patients with high TUBA1C expression exhibit a greater tumor mutation burden and increased genetic variation, which causes a worse prognosis. Additionally, TUBA1C dependency and its effects were evident in kidney cancer cell lines, where mutations conferred resistance to anti-PD-L1 therapy. knockout analyses indicated that treatment targeting TUBA1C shifted malignant cells to a state responsive to ICB therapy. Immunohistochemistry, RT-qPCR and clinical cohort validation further confirmed that TUBA1C expression was upregulated and contributed to poorer outcome in ccRCC. Finaly, wound healing and CCK-8 assays demonstrated the potent oncogenic function of TUBA1C. TUBA1C is a pivotal regulator in ccRCC, affecting both disease progression and the effectiveness of ICB therapy by fostering an immunosuppressive microenvironment mediated by the PI3K/AKT pathway. Additionally, TUBA1C holds promise, both as a prognostic biomarker and a therapeutic target, for enhancing responsiveness to ICB.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: 1-Phosphatidylinositol 3-kinase / AKT protein / Algorithms / Biomarkers / Biomarkers, Tumor - genetics / Cancer therapies / Carcinoma, Renal Cell - drug therapy / Carcinoma, Renal Cell - genetics / Carcinoma, Renal Cell - immunology / Cell cycle / Cell Line, Tumor / Cholecystokinin / Chromosomes / clear cell renal cell carcinoma / Clear cell-type renal cell carcinoma / Datasets / Deep learning / Disease progression / Drug Resistance, Neoplasm - genetics / Female / Gene expression / Gene Expression Regulation, Neoplastic / Genetic diversity / Humans / immune checkpoint blockade / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immunohistochemistry / Immunology / Immunoregulation / Immunosuppressive agents / immunosuppressive tumor microenvironment / immunotherapy resistance / Infiltration / Kidney cancer / Kidney Neoplasms - drug therapy / Kidney Neoplasms - genetics / Kidney Neoplasms - immunology / Kidney Neoplasms - pathology / Kinases / Lymphocytes T / Male / Medical prognosis / Metastases / Metastasis / Mortality / Mutation / Patients / PD-L1 protein / Prognosis / single cell RNA sequencing / Suppressor cells / Therapeutic targets / tubulin alpha 1c / Tumor cell lines / Tumor microenvironment / Tumor Microenvironment - immunology / Tumors / Wound healing