Journal
FRONTIERS IN IMMUNOLOGY
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.971142
Keywords
ccRCC; cuproptosis; immunotherapy; immune checkpoint inhibitors; prognosis; targeted therapy
Categories
Funding
- Scientific Research Foundation of Qilu Hospital of Shandong University (Qingdao) [QDKY2019QN17]
- National Natural Science Foundation of China [82103557, 81972475]
- Shandong Provincial Natural Science Foundation [ZR2020QH245]
- Swedish Cancer Society [19 0018 Pj]
- Swedish Research Council [2018-02993]
- Cancer Society in Stockholm [201393]
- Karolinska Institutet [2018-01524]
- Swedish Research Council [2018-02993] Funding Source: Swedish Research Council
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This study identified the clinical implications of cuproptosis in clear cell renal cell carcinoma (ccRCC) and constructed a gene signature score system (CuAGS-13) that can predict patients' survival, recurrence, and response to treatment.
Cuproptosis, the newly identified form of regulatory cell death (RCD), results from mitochondrial proteotoxic stress mediated by copper and FDX1. Little is known about significances of cuproptosis in oncogenesis. Here we determined clinical implications of cuproptosis in clear cell renal cell carcinoma (ccRCC). Based on the correlation and survival analyses of cuproptosis-correlated genes in TCGA ccRCC cohort, we constructed a cuproptosis-associated 13 gene signature (CuAGS-13) score system. In both TCGA training and two validation cohorts, when patients were categorized into high- and low-risk groups according to a median score as the cutoff, the CuAGS-13 high-risk group was significantly associated with shorter overall survival (OS) and/or progression-free survival (PFS) independently (P<0.001 for all). The CuAGS-13 score assessment could also predict recurrence and recurrence-free survival of patients at stage I - III with a high accuracy, which outperformed the ccAccB/ClearCode34 model, a well-established molecular predictor for ccRCC prognosis. Moreover, patients treated with immune checkpoint inhibitors (ICIs) acquired complete/partial remissions up to 3-time higher coupled with significantly longer PFS in the CuAGS-13 low- than high-risk groups in both training and validation cohorts of ccRCCs (7.2 - 14.1 vs. 2.1 - 3.0 months, P<0.001). The combination of ICI with anti-angiogenic agent Bevacizumab doubled remission rates in CuAGS-13 high-risk patients while did not improve the efficacy in the low-risk group. Further analyses showed a positive correlation between CuAGS-13 and TIDE scores. We also observed that the CuAGS-13 score assessment accurately predicted patient response to Sunitinib, and higher remission rates in the low-risk group led to longer PFS (Low- vs. high-risk, 13.9 vs. 5.8 months, P = 5.0e-12). Taken together, the CuAGS-13 score assessment serves as a robust predictor for survival, recurrence, and response to ICIs, ICI plus anti-angiogenic drugs and Sunitinib in ccRCC patients, which significantly improves patient stratifications for precision medicine of ccRCC.
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