Chinese Medical Sciences Journal ›› 2024, Vol. 39 ›› Issue (2): 111-121.doi: 10.24920/004354
• Research Articles • Previous Articles Next Articles
Jun-Jie Ma1#, Lei Zhang2#, Jin Lu3, 4, Hao-Xuan Zhang3, 4, *()
Received:
2024-03-04
Accepted:
2024-04-18
Published:
2024-06-30
Online:
2024-06-18
Contact:
* About author:
#co-first author:Contributed equally to this work.
Jun-Jie Ma, Lei Zhang, Jin Lu, Hao-Xuan Zhang. PPP1R14A is Associated with Immunotherapy Resistance in Head and Neck Squamous Cell Carcinoma Identified by Single-Cell and Bulk RNA-Sequencing[J].Chinese Medical Sciences Journal, 2024, 39(2): 111-121.
Add to citation manager EndNote|Reference Manager|ProCite|BibTeX|RefWorks
Figure 1.
Identification of nivolumab resistance-associated differentially expressed genes (DEGs) between nivolumab resistant and sensitive patients in the Gene Expression Omnibus (GEO) database. (A) Volcano plot of DEGs between nivolumab resistant and sensitive patients in single-cell and bulk RNA-sequencing data. (B) Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of function annotation of DEGs. (C) Gene set enrichment analysis (GSEA) of biological function of DEGs. (D) The Uniform Manifold Approximation and Projection (UMAP) method shows the distribution of five immune-infiltrating cells in tumor tissues. (E, F) Scatter plot (E) and violin plot (F) of resistance-related scores for five immune-infiltrating cells in tumor tissues (n = 26,324)."
Figure 2.
Identification of key genes for drug resistance. (A, B) Screening of key genes for drug resistance using the Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis (A) and Recursive Feature Elimination (RFE) algorithm analysis (B). (C) Venn diagram shows overlapping DEGs identified by RFE and LASSO. (D, E) Comparisons of expression of each key gene in the sensitive patients (D, n = 42) and the resistant patients (E, n = 54) before and after nivolumab immunotherapy. ***P < 0.001, **P < 0.01, *P < 0.05."
Figure 3.
Correlation of PPP1R14A gene expression and immune response. (A) Differences in tumor purity and immune score between the high and low PPP1R14A gene expression groups (n = 96, *P < 0.05, **P < 0.01). (B) Correlation between PPP1R14A expression and immune cell infiltration. (C) Heatmap of the correlation between PPP1R14A gene and immunoregulatory genes. (D) Expression of PPP1R14A gene in five types of immune cells (n = 9,347). (E) Comparisons of PPP1R14A gene expression in five immune cell subtypes between the nivolumab resistant group and the nivolumab sensitive group (n = 9,347, *P < 0.05, ***P < 0.001). (F) Scatter plot of UMAP distribution of T cell subtypes. (G) Proportion of T cells in different immunotherapy response groups (χ2 = 33.56, P < 0.001). (H) Differential PPP1R14A expression in CD8+ cells, CD4+ cells, and regulatory T cells (Tregs) in the immunotherapy sensitive and resistant groups. (*P < 0.05, ***P < 0.001)."
Figure 4.
The funicton enrichment of PPP1R14A. (A) Heatmap of gene set variation analysis (GSVA) scores for 84 metabolism pathways in the high and low PPP1R14A expression groups. (B) Distribution of GSVA scores of different metabolism pathways in the high and low PPP1R14A expression groups (n = 53, *P < 0.05, **P < 0.01, ***P < 0.001)."
Figure 5.
Identification of pseudotime and cellular communication of immune cells infiltrated in tumor tissues on single cell dataset. (A) Cellular heterogeneity identification with CytoTRACE method. (B) Cellular heterogeneity identification with Monocel3. (C, D) Comparisons of CytoTRACE score (C) and pseudotime score (D) between the high and low PPP1R14A gene expression groups (***P < 0.001). (E) Potential ligand-receptor communication associated with PPP1R14A. (F) GSEA analysis of the MHC-Ⅰ and MHC-Ⅱ pathways associated with PPP1R14A expression."
Figure 6.
Screening potentially sensitive drug for nivolumab resistant HNSCC patients. (A) The correlation between PPP1R14A gene expression and the half maximal inhibitory concentration (IC50) of 565 FDA approved immunotherapeutics. (B, C) Comparisons of IC50 of AXITINIB in bulk (B) and single-cell (C) sequencing data between the high and low PPP1R14A expression groups (***P < 0.001). (D) Scatter plots of IC50 of AXITINIB for immune cells."
Figure 7.
Validation of PPP1R14A expression in external cohorts. (A) The tumor immune dysfunction and exclusion (TIDE) score distribution of the TCGA cohort samples. (B) Correlation between the PPP1R14A expression and TIDE scores in the nivolumab-sensitive and -resistant groups. (C) Differential PPP1R14A expression in nivolumab-sensitive and -resistant groups in the TCGA (n = 552), GSE21551 (n = 100), and GSE226134 (n = 49) cohorts. (*P < 0.05, ***P < 0.001). (D) Relationship between PPP1R14A expression and immunotherapy response in the TCGA, GSE21551, and GSE226134 cohorts."
1. |
Zhao X, Mai Z, Liu L, et al. Hypoxia-driven TNS4 fosters HNSCC tumorigenesis by stabilizing integrin α5β1 complex and triggering FAK-mediated Akt and TGFβ signaling pathways. Int J Biol Sci 2024; 20(1):231-48. doi: 10.7150/ijbs.86317.
pmid: 38164166 |
2. |
Guo X, Xu L, Nie L, et al. B cells in head and neck squamous cell carcinoma: current opinion and novel therapy. Cancer Cell Int 2024; 24(1):41. doi: 10.1186/s12935-024-03218-3.
pmid: 38245714 |
3. | Mathan SV, Singh R, Kim SH, et al. Diallyl trisulfide induces ROS-mediated mitotic arrest and apoptosis and inhibits HNSCC tumor growth and cancer stemness. Cancers (Basel) 2024; 16(2):378. doi: 10.3390/cancers16020378. |
4. |
Liu S, Wang R, Fang J. Exploring the frontiers: tumor immune microenvironment and immunotherapy in head and neck squamous cell carcinoma. Discov Oncol 2024; 15(1):22, doi: 10.1007/s12672-024-00870-z.
pmid: 38294629 |
5. | Gong X, Xiong J, Gong Y, et al. Deciphering the role of HPV-mediated metabolic regulation in shaping the tumor microenvironment and its implications for immunotherapy in HNSCC. Front Immunol 2023; 14:1275270. doi: 10.3389/fimmu.2023.1275270. |
6. | Li C, Guo H, Zhai P, et al. Spatial and single-cell transcriptomics reveal a cancer-associated fibroblast subset in HNSCC that restricts infiltration and antitumor activity of CD8+ T cells. Cancer Res 2024; 84(2):258-75. doi: 10.1158/0008-5472.Can-23-1448. |
7. | Han X, Zhang H, Sun K, et al. Durvalumab with or without tremelimumab for patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a systematic review and meta-analysis. Front Immunol 2023; 14:1302840. doi: 10.3389/fimmu.2023.1302840. |
8. | Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 2015; 43(7):e47. doi: 10.1093/nar/gkv007. |
9. |
Stuart T, Butler A, Hoffman P, et al. Comprehensive integration of single-cell data. Cell 2019; 177(7):1888-902.e21. doi: 10.1016/j.cell.2019.05.031.
pmid: 31178118 |
10. | Andreatta M, Carmona SJ. UCell: robust and scalable single-cell gene signature scoring. Comput Struct Biotechnol J 2021; 19:3796-8. doi: 10.1016/j.csbj.2021.06.043. |
11. | Wu T, Hu E, Xu S, et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innovation (Camb) 2021; 2(3):100141. doi: 10.1016/j.xinn.2021.100141. |
12. |
Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102(43):15545-50. doi: 10.1073/pnas.0506580102.
pmid: 16199517 |
13. |
Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 2013; 14:7. doi: 10.1186/1471-2105-14-7.
pmid: 23323831 |
14. | Tibshirani R. Regression shrinkage and selection via the Lasso. J Royal Statistical Society: Series B (Methodological) 1996; 58(1):267-88. |
15. |
Han Y, Huang L, Zhou F. A dynamic recursive feature elimination framework (dRFE) to further refine a set of OMIC biomarkers. Bioinformatics 2021; 37(15):2183-9. doi: 10.1093/bioinformatics/btab055.
pmid: 33515240 |
16. |
Newman AM, Liu CL, Green MR, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 2015; 12(5):453-7. doi: 10.1038/nmeth.3337.
pmid: 25822800 |
17. |
Yoshihara K, Shahmoradgoli M, Martínez E, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 2013; 4:2612. doi: 10.1038/ncomms3612.
pmid: 24113773 |
18. |
Gulati GS, Sikandar SS, Wesche DJ, et al. Single-cell transcriptional diversity is a hallmark of developmental potential. Science 2020; 367(6476):405-11. doi: 10.1126/science.aax0249.
pmid: 31974247 |
19. | Cao J, Spielmann M, Qiu X, et al. The single-cell transcriptional landscape of mammalian organogenesis. Nature 2019; 566(7745):496-502. doi: 10.1038/s41586-019-0969-x. |
20. |
Lai Y, Lu X, Liao Y, et al. Crosstalk between glioblastoma and tumor microenvironment drives proneural-mesenchymal transition through ligand-receptor interactions. Genes Dis 2024; 11(2):874-89. doi: 10.1016/j.gendis.2023.05.025.
pmid: 37692522 |
21. |
Jin S, Guerrero-Juarez CF, Zhang L, et al. Inference and analysis of cell-cell communication using CellChat. Nat Commun 2021; 12(1):1088. doi: 10.1038/s41467-021-21246-9.
pmid: 33597522 |
22. | Maeser D, Gruener RF, Huang RS. oncoPredict: an R package for predicting in vivo or cancer patient drug response and biomarkers from cell line screening data. Brief Bioinform 2021; 22(6):bbab260. doi: 10.1093/bib/bbab260. |
23. |
Fustero-Torre C, Jiménez-Santos MJ, García-Martín S, et al. Beyondcell: targeting cancer therapeutic heterogeneity in single-cell RNA-seq data. Genome Med 2021; 13(1):187. doi: 10.1186/s13073-021-01001-x.
pmid: 34911571 |
24. |
Fu J, Li K, Zhang W, et al. Large-scale public data reuse to model immunotherapy response and resistance. Genome Med 2020; 12(1):21. doi: 10.1186/s13073-020-0721-z.
pmid: 32102694 |
25. | Zhao X, Guo B, Sun W, et al. Targeting squalene epoxidase confers metabolic vulnerability and overcomes chemoresistance in HNSCC. Adv Sci (Weinh) 2023; 10(27):e2206878. doi: 10.1002/advs.202206878. |
26. | Guo Y, Nakashima T, Cho BC, et al. Clinical decision pathway and management of locally advanced head and neck squamous cell carcinoma: a multidisciplinary consensus in Asia-Pacific. Oral Oncol 2024; 148:106657. doi: 10.1016/j.oraloncology.2023.106657. |
27. | Runnels J, Bloom JR, Hsieh K, et al. Combining radiotherapy and immunotherapy in head and neck cancer. Biomedicines 2023; 11(8):2097. doi: 10.3390/biomedicines11082097. |
28. | Zhang J, Joshua AM, Li Y, et al. Targeted therapy, immunotherapy, and small molecules and peptidomimetics as emerging immunoregulatory agents for melanoma. Cancer Lett 2024; 586:216633. doi: 10.1016/j.canlet.2024.216633. |
29. | Yin J, Gu T, Chaudhry N, et al. Epigenetic modulation of antitumor immunity and immunotherapy response in breast cancer: biological mechanisms and clinical implications. Front Immunol 2023; 14:1325615. doi: 10.3389/fimmu.2023.1325615. |
30. | Iwasa YI, Nakajima T, Hori K, et al. A spatial transcriptome reveals changes in tumor and tumor microenvironment in oral cancer with acquired resistance to immunotherapy. Biomolecules 2023; 13(12):1685. doi: 10.3390/biom13121685. |
31. | Meliante PG, Zoccali F, de Vincentiis M, et al. Diagnostic predictors of immunotherapy response in head and neck squamous cell carcinoma. Diagnostics (Basel) 2023; 13(5):862. doi: 10.3390/diagnostics13050862. |
32. | Wei F, Fang R, Lyu K, et al. Exosomal PD-L1 derived from head and neck squamous cell carcinoma promotes immune evasion by activating the positive feedback loop of activated regulatory T cell-M2 macrophage. Oral Oncol 2023; 145: 106532. doi: 10.1016/j.oraloncology.2023.106532. |
33. | Jin Y, Qin X. Profiles of immune cell infiltration and their clinical significance in head and neck squamous cell carcinoma. Int Immunopharmacol 2020; 82:106364. doi: 10.1016/j.intimp.2020.106364. |
34. | Bao J, Betzler AC, Hess J, et al. Exploring the dual role of B cells in solid tumors: implications for head and neck squamous cell carcinoma. Front Immunol 2023; 14:1233085. doi: 10.3389/fimmu.2023.1233085. |
35. | Stelzer G, Rosen N, Plaschkes I, et al. The GeneCards suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinformatics 2016; 54:1.30.1-1.30.33. doi: 10.1002/cpbi.5. |
36. | Thul PJ, Akesson L, Wiking M, et al. A subcellular map of the human proteome. Science 2017; 356(6340):eaal3321. doi: 10.1126/science.aal3321. |
37. | Wang Z, Huang R, Wang H, et al. Prognostic and immunological role of PPP1R14A as a Pan-cancer analysis candidate. Front Genet 2022; 13:842975. doi: 10.3389/fgene.2022.842975. |
38. | Tian Y, Soupir A, Liu Q, et al. Novel role of prostate cancer risk variant rs 7247241 on PPP1R14A isoform transition through allelic TF binding and CpG methylation. Hum Mol Genet 2022; 31(10):1610-21. doi: 10.1093/hmg/ddab347. |
39. | Liu L, Zhu H, Wang P, et al. Construction of a six-gene prognostic risk model related to hypoxia and angiogenesis for cervical cancer. Front Genet 2022; 13:923263. doi: 10.3389/fgene.2022.923263. |
40. | Yu QS, Feng WQ, Shi LL, et al. Integrated analysis of cortex single-cell transcriptome and serum proteome reveals the novel biomarkers in Alzheimer's disease. Brain Sci 2022; 12(8):1022. doi: 10.3390/brainsci12081022. |
41. |
Zou W, Green DR. Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy. Cell Metab 2023; 35(7):1101-13. doi: 10.1016/j.cmet.2023.06.003.
pmid: 37390822 |
42. | Liu N, Yan M, Tao Q, et al. Inhibition of TCA cycle improves the anti-PD-1 immunotherapy efficacy in melanoma cells via ATF3-mediated PD-L 1 expression and glycolysis. J Immunother Cancer 2023; 11(9):e007146. doi: 10.1136/jitc-2023-007146. |
43. | Yang L, Chu Z, Liu M, et al. Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy. J Hematol Oncol 2023; 16(1):59. doi: 10.1186/s13045-023-01453-1. |
44. |
Liu Y, Li S, Wang S, et al. LIMP-2 enhances cancer stem-like cell properties by promoting autophagy-induced GSK3β degradation in head and neck squamous cell carcinoma. Int J Oral Sci 2023; 15(1):24. doi: 10.1038/s41368-023-00229-0.
pmid: 37291150 |
45. |
Swiecicki PL, Spector M, Worden FP. Axitinib in the treatment of head and neck malignancies. Curr Clin Pharmacol 2016; 11(2): 72-6. doi: 10.2174/1574884711666160518120622.
pmid: 27188575 |
46. |
Swiecicki PL, Bellile EL, Brummel CV, et al. Efficacy of axitinib in metastatic head and neck cancer with novel radiographic response criteria. Cancer 2021; 127(2):219-28. doi: 10.1002/cncr.33226.
pmid: 33079405 |
[1] | Hao-Ling Li, Jun-Xian Wang, Heng-Wen Dai, Jun-Jie Liu, Zi-Yang Liu, Ming-Yuan Zou, Lei Zhang, Wen-Rui Wang. Prognostic Prediction Value and Biological Functions of Non-Apoptotic Regulated Cell Death Genes in Lung Adenocarcinoma [J]. Chinese Medical Sciences Journal, 2023, 38(3): 178-190. |
[2] | Liu Zhengzheng, Kuang Weilu, Zeng Wenjing, Xiao Jianyun, Tian Yongquan. Downregulation of iASPP Expression Suppresses Proliferation, Invasion and Increases Chemosensitivity to Paclitaxel of Head and Neck Squamous Cell Carcinoma In Vitro [J]. Chinese Medical Sciences Journal, 2019, 34(3): 184-193. |
[3] | Ni Jieming, Ni Anping. Landscape of PD-1/PD-L1 Regulation and Targeted Immunotherapy [J]. Chinese Medical Sciences Journal, 2018, 33(3): 174-182. |
[4] | Zhao Zhimei, Liu Shichao, Xu Xiajuan, Zhang Zhongfa, Nie Keke, Ji Youxin. Treatment of Skin Reaction Induced by Nivolumab Combined with Radiotherapy in Non-small Cell Lung Cancer: A Case Report [J]. Chinese Medical Sciences Journal, 2018, 33(3): 183-187. |
[5] | Ling Li, Hong-jie Li, Jian-sheng zhi, Hong Chen, Wen-li Xie. ZM-66, a New Podophyllotoxin Derivative Inhibits Proliferation and Induces Apoptosis in K562/ADM Cells [J]. Chinese Medical Sciences Journal, 2014, 29(3): 174-179. |
Viewed | ||||||
Full text |
|
|||||
Abstract |
|
|||||
|
Supervised by National Health Commission of the People's Republic of China
9 Dongdan Santiao, Dongcheng district, Beijing, 100730 China
Tel: 86-10-65105897 Fax:86-10-65133074
E-mail: cmsj@cams.cn www.cmsj.cams.cn
Copyright © 2018 Chinese Academy of Medical Sciences
All right reserved.
京公安备110402430088 京ICP备06002729号-1