AUTHOR=Cai Yonghua , Liang Xianqiu , Zhan Zhengming , Zeng Yu , Lin Jie , Xu Anqi , Xue Shuaishuai , Xu Wei , Chai Peng , Mao Yangqi , Song Zibin , Han Lei , Xiao Jianqi , Song Ye , Zhang Xian 

TITLE=A Ferroptosis-Related Gene Prognostic Index to Predict Temozolomide Sensitivity and Immune Checkpoint Inhibitor Response for Glioma

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.812422

DOI=10.3389/fcell.2021.812422

ISSN=2296-634X

ABSTRACT=<p><bold>Background:</bold> Gliomas are highly lethal brain tumors. Despite multimodality therapy with surgery, radiotherapy, chemotherapy, and immunotherapy, glioma prognosis remains poor. Ferroptosis is a crucial tumor suppressor mechanism that has been proven to be effective in anticancer therapy. However, the implications of ferroptosis on the clinical prognosis, chemotherapy, and immune checkpoint inhibitor (ICI) therapy for patients with glioma still need elucidation.</p><p><bold>Methods:</bold> Consensus clustering revealed two distinct ferroptosis-related subtypes based on the Cancer Genome Atlas (TCGA) glioma dataset (<italic>n</italic> = 663). Subsequently, the ferroptosis-related gene prognostic index (FRGPI) was constructed by weighted gene co-expression network analysis (WGCNA) and “stepAIC” algorithms and validated with the Chinese Glioma Genome Atlas (CGGA) dataset (<italic>n</italic> = 404). Subsequently, the correlation among clinical, molecular, and immune features and FRGPI was analyzed. Next, the temozolomide sensitivity and ICI response for glioma were predicted using the “pRRophetic” and “TIDE” algorithms, respectively. Finally, candidate small molecular drugs were defined using the connectivity map database based on FRGPI.</p><p><bold>Results:</bold> The FRGPI was established based on the <italic>HMOX1</italic>, <italic>TFRC</italic>, <italic>JUN</italic>, and <italic>SOCS1</italic> genes. The distribution of FRGPI varied significantly among the different ferroptosis-related subtypes. Patients with high FRGPI had a worse overall prognosis than patients with low FRGPI, consistent with the results in the CGGA dataset. The final results showed that high FRGPI was characterized by more aggressive phenotypes, high <italic>PD-L1</italic> expression, high tumor mutational burden score, and enhanced temozolomide sensitivity; low FRGPI was associated with less aggressive phenotypes, high microsatellite instability score, and stronger response to immune checkpoint blockade. In addition, the infiltration of memory resting CD4<sup>+</sup> T cells, regulatory T cells, M1 macrophages, M2 macrophages, and neutrophils was positively correlated with FRGPI. In contrast, plasma B cells and naïve CD4<sup>+</sup> T cells were negatively correlated. A total of 15 potential small molecule compounds (such as depactin, physostigmine, and phenacetin) were identified.</p><p><bold>Conclusion:</bold> FRGPI is a promising gene panel for predicting the prognosis, immune characteristics, temozolomide sensitivity, and ICI response in patients with glioma.</p>