A Four-Gene Autophagy-Related Prognostic Model Signature and Its Association With Immune Phenotype in Lung Squamous Cell Carcinoma

Overview

Journal Cancer Rep (Hoboken)

Specialty Oncology

Date 2024 Oct 24

PMID 39443755

Authors

Lumeng Luo

Jiaying Deng

Qiu Tang

Affiliations

Soon will be listed here.

Abstract

Background: In the era of immunotherapy, there is a critical need for effective biomarkers to improve outcome prediction and guide treatment decisions for patients with lung squamous cell carcinoma (LUSC). We hypothesized that the immune contexture of LUSC may be influenced by tumor intrinsic events, such as autophagy.

Aims: We aimed to develop an autophagy-related risk signature and assess its predictive value for immune phenotype.

Methods And Results: Expression profiles of autophagy-related genes (ARGs) in LUSC samples were obtained from the TCGA and GEO databases. Survival analyses were conducted to identify survival-related ARGs and construct a risk signature using the Random Forest algorithm. Four ARGs (CFLAR, RGS19, PINK1, and CTSD) with the most significant prognostic value were selected to construct the risk signature. Patients in the high-risk group exhibited worse prognosis than those in the low-risk group (p < 0.0001 in TCGA; p < 0.01 in GEO) and the risk score was identified as an independent prognostic factor. We observed that the high-risk group displayed an immune-suppressive status and showed higher levels of infiltrating regulatory T cells and macrophages, which are associated with poorer outcomes. Additionally, the risk score exhibited a significantly positive correlation with the expression of PD-1 and CTLA4, as well as the estimate score and immune score.

Conclusion: This study provided an effective autophagy-related prognostic signature, which could also predict the immune phenotype.

Citing Articles

Construction of the bromodomain-containing protein-associated prognostic model in triple-negative breast cancer.

Chen W, Yu Y, Wang C, Jiang Z, Huang X, Lin Y Cancer Cell Int. 2025; 25(1):18.

PMID: 39827145 PMC: 11742518. DOI: 10.1186/s12935-025-03648-7.

References

Safa A, Pollok K . Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy. Cancers (Basel). 2012; 3(2):1639-71. PMC: 3281420. DOI: 10.3390/cancers3021639. View

Teng M, Ngiow S, Ribas A, Smyth M . Classifying Cancers Based on T-cell Infiltration and PD-L1. Cancer Res. 2015; 75(11):2139-45. PMC: 4452411. DOI: 10.1158/0008-5472.CAN-15-0255. View

Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A . Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003; 112(12):1809-20. PMC: 297002. DOI: 10.1172/JCI20039. View

Jia Q, Wu W, Wang Y, Alexander P, Sun C, Gong Z . Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer. Nat Commun. 2018; 9(1):5361. PMC: 6299138. DOI: 10.1038/s41467-018-07767-w. View

Hamdy N, Suwailem S, El-Mesallamy H . Influence of vitamin E supplementation on endothelial complications in type 2 diabetes mellitus patients who underwent coronary artery bypass graft. J Diabetes Complications. 2008; 23(3):167-73. DOI: 10.1016/j.jdiacomp.2007.10.006. View

Shibutani S, Saitoh T, Nowag H, Munz C, Yoshimori T . Autophagy and autophagy-related proteins in the immune system. Nat Immunol. 2015; 16(10):1014-24. DOI: 10.1038/ni.3273. View

Maleki Vareki S . High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J Immunother Cancer. 2018; 6(1):157. PMC: 6307306. DOI: 10.1186/s40425-018-0479-7. View

Amaravadi R, Kimmelman A, Debnath J . Targeting Autophagy in Cancer: Recent Advances and Future Directions. Cancer Discov. 2019; 9(9):1167-1181. PMC: 7306856. DOI: 10.1158/2159-8290.CD-19-0292. View

Hah Y, Noh H, Ha J, Ahn J, Hahm J, Cho H . Cathepsin D inhibits oxidative stress-induced cell death via activation of autophagy in cancer cells. Cancer Lett. 2012; 323(2):208-14. DOI: 10.1016/j.canlet.2012.04.012. View

10.

Emam O, Wasfey E, Hamdy N . Notch-associated lncRNAs profiling circuiting epigenetic modification in colorectal cancer. Cancer Cell Int. 2022; 22(1):316. PMC: 9558410. DOI: 10.1186/s12935-022-02736-2. View

11.

Hsu S, Li C, Lin I, Syue W, Chen Y, Cheng K . Inflammation-related pyroptosis, a novel programmed cell death pathway, and its crosstalk with immune therapy in cancer treatment. Theranostics. 2021; 11(18):8813-8835. PMC: 8419056. DOI: 10.7150/thno.62521. View

12.

McLornan D, Barrett H, Cummins R, McDermott U, McDowell C, Conlon S . Prognostic significance of TRAIL signaling molecules in stage II and III colorectal cancer. Clin Cancer Res. 2010; 16(13):3442-51. PMC: 2896551. DOI: 10.1158/1078-0432.CCR-10-0052. View

13.

Bianco A, Perrotta F, Barra G, Malapelle U, Rocco D, De Palma R . Prognostic Factors and Biomarkers of Responses to Immune Checkpoint Inhibitors in Lung Cancer. Int J Mol Sci. 2019; 20(19). PMC: 6801651. DOI: 10.3390/ijms20194931. View

14.

Wang Z, Jensen M, Zenklusen J . A Practical Guide to The Cancer Genome Atlas (TCGA). Methods Mol Biol. 2016; 1418:111-41. DOI: 10.1007/978-1-4939-3578-9_6. View

15.

Liu G, Pei F, Yang F, Li L, Amin A, Liu S . Role of Autophagy and Apoptosis in Non-Small-Cell Lung Cancer. Int J Mol Sci. 2017; 18(2). PMC: 5343902. DOI: 10.3390/ijms18020367. View

16.

Tso P, Yung L, Wang Y, Wong Y . RGS19 stimulates cell proliferation by deregulating cell cycle control and enhancing Akt signaling. Cancer Lett. 2011; 309(2):199-208. DOI: 10.1016/j.canlet.2011.06.002. View

17.

Siegel R, Miller K, Jemal A . Cancer statistics, 2018. CA Cancer J Clin. 2018; 68(1):7-30. DOI: 10.3322/caac.21442. View

18.

Guo J, Teng X, Laddha S, Ma S, Van Nostrand S, Yang Y . Autophagy provides metabolic substrates to maintain energy charge and nucleotide pools in Ras-driven lung cancer cells. Genes Dev. 2016; 30(15):1704-17. PMC: 5002976. DOI: 10.1101/gad.283416.116. View

19.

Micheau O . Cellular FLICE-inhibitory protein: an attractive therapeutic target?. Expert Opin Ther Targets. 2003; 7(4):559-73. PMC: 2984612. DOI: 10.1517/14728222.7.4.559. View

20.

Tang R, Xu J, Zhang B, Liu J, Liang C, Hua J . Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J Hematol Oncol. 2020; 13(1):110. PMC: 7418434. DOI: 10.1186/s13045-020-00946-7. View