Top

Published in:

01-12-2021 | Lung Cancer | Research article

m⁶A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer

Authors: Zhihui Zhang, Chaoqi Zhang, Yuejun Luo, Peng Wu, Guochao Zhang, Qingpeng Zeng, Lide Wang, Zhaoyang Yang, Liyan Xue, Bo Zheng, Hua Zeng, Fengwei Tan, Qi Xue, Shugeng Gao, Nan Sun, Jie He

Published in: BMC Medicine | Issue 1/2021

Abstract

Background

Small cell lung cancer (SCLC) is lethal and possesses limited therapeutic options. Platinum-based chemotherapy—with or without immune checkpoint inhibitors (anti-PDs)—is the current first-line therapy for SCLCs; however, its associated outcomes are heterogeneous. N⁶-methyladenosine (m⁶A) is a novel and decisive factor in tumour progression, chemotherapy resistance, and immunotherapy response. However, m⁶A modification in SCLC remains poorly understood.

Methods

We systematically explored the molecular features and clinical significance of m⁶A regulators in SCLC. We then constructed an m⁶A regulator-based prognostic signature (m⁶A score) based on our examination of 256 cases with limited-stage SCLC (LS-SCLC) from three different cohorts—including an independent cohort that contained 150 cases with qPCR data. We additionally evaluated the relationships between the m⁶A score and adjuvant chemotherapy (ACT) benefits and the patients’ responses to anti-PD-1 treatment. Immunohistochemical (IHC) staining and the HALO digital pathological platform were used to calculate CD8+ T cell density.

Results

We observed abnormal somatic mutations and expressions of m⁶A regulators. Using the LASSO Cox model, a five-regulator-based (G3BP1, METTL5, ALKBH5, IGF2BP3, and RBM15B) m⁶A score was generated from the significant regulators to classify patients into high- and low-score groups. In the training cohort, patients with high scores had shorter overall survival (HR, 5.19; 2.75–9.77; P < 0.001). The prognostic accuracy of the m⁶A score was well validated in two independent cohorts (HR 4.6, P = 0.006 and HR 3.07, P < 0.001). Time-dependent ROC and C-index analyses found the m⁶A score to possess superior predictive power than other clinicopathological parameters. A multicentre multivariate analysis revealed the m⁶A score to be an independent prognostic indicator. Additionally, patients with low scores received a greater survival benefit from ACT, exhibited more CD8+ T cell infiltration, and were more responsive to cancer immunotherapy.

Conclusions

Our results, for the first time, affirm the significance of m⁶A regulators in LS-SCLC. Our multicentre analysis found that the m⁶A score was a reliable prognostic tool for guiding chemotherapy and immunotherapy selections for patients with SCLC.

Available only for authorised users

van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet (London, England). 2011;378(9804):1741–55.CrossRef

Gazdar AF, Minna JD. Developing new, rational therapies for recalcitrant small cell lung cancer. J Natl Cancer Inst. 2016;108(10):djw119. https://doi.org/10.1093/jnci/djw119.CrossRefPubMed

Alvarado-Luna G, Morales-Espinosa D. Treatment for small cell lung cancer, where are we now?-a review. Transl Lung Cancer Res. 2016;5(1):26–38. https://doi.org/10.3978/j.issn.2218-6751.2016.01.13.CrossRefPubMedPubMedCentral

Welsh JW, Heymach JV, Guo C, Menon H, Klein K, Cushman TR, et al. Phase 1/2 trial of pembrolizumab and concurrent chemoradiation therapy for limited-stage SCLC. J Thorac Oncol. 2020;15(12):1919–27.CrossRefPubMed

Gong J, Chehrazi-Raffle A, Reddi S, Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer. 2018;6(1):8. https://doi.org/10.1186/s40425-018-0316-z.CrossRefPubMedPubMedCentral

Roviello G, Corona SP, Nesi G, Mini E. Results from a meta-analysis of immune checkpoint inhibitors in first-line renal cancer patients: does PD-L1 matter? Ther Adv Med Oncol. 2019;11:1758835919861905. https://doi.org/10.1177/1758835919861905.CrossRefPubMedPubMedCentral

Lei Q, Wang D, Sun K, Wang L, Zhang Y. Resistance mechanisms of anti-PD1/PDL1 therapy in solid tumors. Front Cell Dev Biol. 2020;8:672. https://doi.org/10.3389/fcell.2020.00672.CrossRefPubMedPubMedCentral

Zhang C, Zhang Z, Sun N, Zhang Z, Zhang G, Wang F, et al. Identification of a costimulatory molecule-based signature for predicting prognosis risk and immunotherapy response in patients with lung adenocarcinoma. Oncoimmunology. 2020;9(1):1824641. https://doi.org/10.1080/2162402X.2020.1824641.CrossRefPubMedPubMedCentral

Lu S, Stein JE, Rimm DL, Wang DW, Bell JM, Johnson DB, et al. Comparison of biomarker modalities for predicting response to PD-1/PD-L1 checkpoint blockade: a systematic review and meta-analysis. JAMA Oncol. 2019;5(8):1195–204. https://doi.org/10.1001/jamaoncol.2019.1549.CrossRefPubMedPubMedCentral

10.

Thommen DS, Koelzer VH, Herzig P, Roller A, Trefny M, Dimeloe S, et al. A transcriptionally and functionally distinct PD-1(+) CD8(+) T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat Med. 2018;24(7):994–1004. https://doi.org/10.1038/s41591-018-0057-z.CrossRefPubMedPubMedCentral

11.

Khan P, Siddiqui JA, Maurya SK, Lakshmanan I, Jain M, Ganti AK, et al. Epigenetic landscape of small cell lung cancer: small image of a giant recalcitrant disease. Semin Cancer Biol. 2020. https://doi.org/10.1016/j.semcancer.2020.11.006.

12.

Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in gene expression regulation. Cell. 2017;169(7):1187–200. https://doi.org/10.1016/j.cell.2017.05.045.CrossRefPubMedPubMedCentral

13.

Wang T, Kong S, Tao M, Ju S. The potential role of RNA N6-methyladenosine in Cancer progression. Mol Cancer. 2020;19(1):88. https://doi.org/10.1186/s12943-020-01204-7.CrossRefPubMedPubMedCentral

14.

Yang Y, Hsu PJ, Chen YS, Yang YG. Dynamic transcriptomic m⁶A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Research. 2018;28(6):616–24. https://doi.org/10.1038/s41422-018-0040-8.CrossRefPubMedPubMedCentral

15.

Pinello N, Sun S, Wong JJ. Aberrant expression of enzymes regulating m⁶A mRNA methylation: implication in cancer. Cancer Biol Med. 2018;15(4):323–34. https://doi.org/10.20892/j.issn.2095-3941.2018.0365.CrossRefPubMedPubMedCentral

16.

Tong J, Cao G, Zhang T, Sefik E, Amezcua Vesely MC, Broughton JP, et al. m⁶A mRNA methylation sustains Treg suppressive functions. Cell Res. 2018;28(2):253–6. https://doi.org/10.1038/cr.2018.7.CrossRefPubMedPubMedCentral

17.

Jin D, Guo J, Wu Y, Du J, Yang L, Wang X, et al. m⁶A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis. J Hematol Oncol. 2019;12(1):135. https://doi.org/10.1186/s13045-019-0830-6.CrossRefPubMedPubMedCentral

18.

Zhou S, Bai ZL, Xia D, Zhao ZJ, Zhao R, Wang YY, et al. FTO regulates the chemo-radiotherapy resistance of cervical squamous cell carcinoma (CSCC) by targeting β-catenin through mRNA demethylation. Mol Carcinog. 2018;57(5):590–7. https://doi.org/10.1002/mc.22782.CrossRefPubMed

19.

Li HB, Tong J, Zhu S, Batista PJ, Duffy EE, Zhao J, et al. m⁶A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature. 2017;548(7667):338–42. https://doi.org/10.1038/nature23450.CrossRefPubMedPubMedCentral

20.

Han D, Liu J, Chen C, Dong L, Liu Y, Chang R, et al. Anti-tumour immunity controlled through mRNA m⁶A methylation and YTHDF1 in dendritic cells. Nature. 2019;566(7743):270–4. https://doi.org/10.1038/s41586-019-0916-x.CrossRefPubMedPubMedCentral

21.

Zhao X, Cui L. Development and validation of a m⁶A RNA methylation regulators-based signature for predicting the prognosis of head and neck squamous cell carcinoma. Am J Cancer Res. 2019;9(10):2156–69.PubMedPubMedCentral

22.

Zhou J, Wang J, Hong B, Ma K, Xie H, Li L, et al. Gene signatures and prognostic values of m6A regulators in clear cell renal cell carcinoma - a retrospective study using TCGA database. Aging. 2019;11(6):1633–47. https://doi.org/10.18632/aging.101856.CrossRefPubMedPubMedCentral

23.

Li Y, Xiao J, Bai J, Tian Y, Qu Y, Chen X, et al. Molecular characterization and clinical relevance of m⁶A regulators across 33 cancer types. Mol Cancer. 2019;18(1):137. https://doi.org/10.1186/s12943-019-1066-3.CrossRefPubMedPubMedCentral

24.

Liu J, Harada BT, He C. Regulation of gene expression by N⁶-methyladenosine in cancer. Trends Cell Biol. 2019;29(6):487–99. https://doi.org/10.1016/j.tcb.2019.02.008.CrossRefPubMedPubMedCentral

25.

Huang H, Weng H, Chen J. m⁶A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell. 2020;37(3):270–88. https://doi.org/10.1016/j.ccell.2020.02.004.CrossRefPubMedPubMedCentral

26.

Nombela P, Miguel-López B, Blanco S. The role of m⁶A, m⁵C and Ψ RNA modifications in cancer: novel therapeutic opportunities. Mol Cancer. 2021;20(1):18. https://doi.org/10.1186/s12943-020-01263-w.CrossRefPubMedPubMedCentral

27.

Wang L, Hui H, Agrawal K, Kang Y, Li N, Tang R, et al. m⁶A RNA methyltransferases METTL3/14 regulate immune responses to anti-PD-1 therapy. EMBO J. 2020;39(20):e104514. https://doi.org/10.15252/embj.2020104514.CrossRefPubMedPubMedCentral

28.

Wang H, Hu X, Huang M, Liu J, Gu Y, Ma L, et al. Mettl3-mediated mRNA m⁶A methylation promotes dendritic cell activation. Nat Commun. 2019;10(1):1898. https://doi.org/10.1038/s41467-019-09903-6.CrossRefPubMedPubMedCentral

29.

Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, et al. m⁶A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31(4):591–606.e596.CrossRefPubMedPubMedCentral

30.

Tang B, Yang Y, Kang M, Wang Y, Wang Y, Bi Y, et al. m⁶A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling. Mol Cancer. 2020;19(1):3. https://doi.org/10.1186/s12943-019-1128-6.CrossRefPubMedPubMedCentral

31.

Jin D, Guo J, Wu Y, Yang L, Wang X, Du J, et al. m⁶A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2-mediated YAP activity in NSCLC. Mol Cancer. 2020;19(1):40. https://doi.org/10.1186/s12943-020-01161-1.CrossRefPubMedPubMedCentral

32.

Su Y, Huang J, Hu J. m⁶A RNA methylation regulators contribute to malignant progression and have clinical prognostic impact in gastric cancer. Front Oncol. 2019;9:1038. https://doi.org/10.3389/fonc.2019.01038.CrossRefPubMedPubMedCentral

33.

Liu X, Liu L, Dong Z, Li J, Yu Y, Chen X, et al. Expression patterns and prognostic value of m⁶A-related genes in colorectal cancer. Am J Transl Res. 2019;11(7):3972–91.PubMedPubMedCentral

34.

Zhuang Z, Chen L, Mao Y, Zheng Q, Li H, Huang Y, et al. Diagnostic, progressive and prognostic performance of m⁶A methylation RNA regulators in lung adenocarcinoma. Int J Biol Sci. 2020;16(11):1785–97. https://doi.org/10.7150/ijbs.39046.CrossRefPubMedPubMedCentral

35.

Lederer M, Bley N, Schleifer C, Hüttelmaier S. The role of the oncofetal IGF2 mRNA-binding protein 3 (IGF2BP3) in cancer. Semin Cancer Biol. 2014;29:3–12. https://doi.org/10.1016/j.semcancer.2014.07.006.CrossRefPubMed

36.

Yang Z, Wang T, Wu D, Min Z, Tan J, Yu B. RNA N6-methyladenosine reader IGF2BP3 regulates cell cycle and angiogenesis in colon cancer. J Exp Clin Cancer Res. 2020;39(1):203.CrossRefPubMedPubMedCentral

37.

Huang W, Li Y, Zhang C, Zha H, Zhou X, Fu B, et al. IGF2BP3 facilitates cell proliferation and tumorigenesis via modulation of JAK/STAT signalling pathway in human bladder cancer. J Cell Mol Med. 2020;24(23):13949–60. https://doi.org/10.1111/jcmm.16003.CrossRefPubMedPubMedCentral

38.

Ji G, Huang C, He S, Gong Y, Song G, Li X, et al. Comprehensive analysis of m6A regulators prognostic value in prostate cancer. Aging. 2020;12(14):14863–84. https://doi.org/10.18632/aging.103549.CrossRefPubMedPubMedCentral

39.

Li W, Li N, Gao L, You C. Integrated analysis of the roles and prognostic value of RNA binding proteins in lung adenocarcinoma. PeerJ. 2020;8:e8509. https://doi.org/10.7717/peerj.8509.CrossRefPubMedPubMedCentral

40.

Li K, Luo H, Luo H, Zhu X. Clinical and prognostic pan-cancer analysis of m6A RNA methylation regulators in four types of endocrine system tumors. Aging. 2020;12(23):23931–44. https://doi.org/10.18632/aging.104064.CrossRefPubMedPubMedCentral

41.

Fang J, Hu M, Sun Y, Zhou S, Li H. Expression profile analysis of m6A RNA methylation regulators indicates they are immune signature associated and can predict survival in kidney renal cell carcinoma. DNA Cell Biol. 2020;39(12):2194–211. https://doi.org/10.1089/dna.2020.5767.CrossRef

42.

Wang Y, Fu D, Chen Y, Su J, Wang Y, Li X, et al. G3BP1 promotes tumor progression and metastasis through IL-6/G3BP1/STAT3 signaling axis in renal cell carcinomas. Cell Death Dis. 2018;9(5):501. https://doi.org/10.1038/s41419-018-0504-2.CrossRefPubMedPubMedCentral

43.

Zheng H, Zhan Y, Zhang Y, Liu S, Lu J, Yang Y, et al. Elevated expression of G3BP1 associates with YB1 and p-AKT and predicts poor prognosis in nonsmall cell lung cancer patients after surgical resection. Cancer Med. 2019;8(16):6894–903. https://doi.org/10.1002/cam4.2579.CrossRefPubMedPubMedCentral

44.

van Tran N, Ernst FGM, Hawley BR, Zorbas C, Ulryck N, Hackert P, et al. The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112. Nucleic Acids Res. 2019;47(15):7719–33. https://doi.org/10.1093/nar/gkz619.CrossRefPubMedPubMedCentral

45.

Sun S, Fei K, Zhang G, Wang J, Yang Y, Guo W, et al. Construction and comprehensive analyses of a METTL5-associated prognostic signature with immune implication in lung adenocarcinomas. Front Genet. 2020;11:617174. https://doi.org/10.3389/fgene.2020.617174.CrossRefPubMed

46.

Shriwas O, Priyadarshini M, Samal SK, Rath R, Panda S, Das Majumdar SK, et al. DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m⁶A-demethylation of FOXM1 and NANOG. Apoptosis. 2020;25(3-4):233–46.CrossRefPubMed

47.

Chen CL, Tsukamoto H, Liu JC, Kashiwabara C, Feldman D, Sher L, et al. Reciprocal regulation by TLR4 and TGF-β in tumor-initiating stem-like cells. J Clin Invest. 2013;123(7):2832–49. https://doi.org/10.1172/JCI65859.CrossRefPubMedPubMedCentral

48.

Zhao J, Fu X, Chen H, Min L, Sun J, Yin J, et al. G3BP1 interacts with YWHAZ to regulate chemoresistance and predict adjuvant chemotherapy benefit in gastric cancer. British J Cancer. 2021;124(2):425–36. https://doi.org/10.1038/s41416-020-01067-1.CrossRef

49.

Iams WT, Porter J, Horn L. Immunotherapeutic approaches for small-cell lung cancer. Nat Rev Clin Oncol. 2020;17(5):300–12. https://doi.org/10.1038/s41571-019-0316-z.CrossRefPubMedPubMedCentral

50.

Li N, Kang Y, Wang L, Huff S, Tang R, Hui H, et al. ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment. Proc Natl Acad Sci U S A. 2020;117(33):20159–70. https://doi.org/10.1073/pnas.1918986117.CrossRefPubMedPubMedCentral

Title: m6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer
Authors: Zhihui Zhang
Chaoqi Zhang
Yuejun Luo
Peng Wu
Guochao Zhang
Qingpeng Zeng
Lide Wang
Zhaoyang Yang
Liyan Xue
Bo Zheng
Hua Zeng
Fengwei Tan
Qi Xue
Shugeng Gao
Nan Sun
Jie He
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Lung Cancer
Lung Cancer
SCLC
Lung Cancer
SCLC
Cytostatic Therapy
Published in: BMC Medicine / Issue 1/2021
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-021-02148-5

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

m⁶A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2021

Discovery and validation of methylation signatures in circulating cell-free DNA for early detection of esophageal cancer: a case-control study

Undernutrition: a major but potentially preventable cause of poor outcomes in children living with sickle cell disease in Africa

Real-world effectiveness of primary screening with high-risk human papillomavirus testing in the cervical cancer screening programme in China: a nationwide, population-based study

Prevalence and predictors of vitamin D deficiency in young African children

COVID-19 and risk of subsequent life-threatening secondary infections: a matched cohort study in UK Biobank

Models of COVID-19 vaccine prioritisation: a systematic literature search and narrative review