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Erschienen in: Investigational New Drugs 1/2022

09.09.2021 | PRECLINICAL STUDIES

KAT2B is an immune infiltration-associated biomarker predicting prognosis and response to immunotherapy in non‐small cell lung cancer

verfasst von: Xue Zhou, Ning Wang, Yuefeng Zhang, Hongzhi Yu, Qi Wu

Erschienen in: Investigational New Drugs | Ausgabe 1/2022

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Summary

Background. Over the past few years, dramatic breakthroughs in the field of tumor immunotherapy with immune checkpoint inhibitors (ICIs) have made a therapeutic revolution for non-small cell lung cancer (NSCLC). While only some patients present a favorable response to this treatment. It is urgent to explore the potential molecular mechanisms underlying the regulation of tumor immune microenvironment in the process of immunotherapy. Lysine acetyltransferase 2B (KAT2B) plays a crucial role in the regulation of gene expression at the post-transcriptional level by acetylation, and is associated with many types of cancer. Methods. RNA-sequencing data, genetic mutation data, and corresponding clinical information were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, then subjected to immune characteristics, gene expression, survival, genetic alteration, enrichment analyses. Results. KAT2B expression correlated positively with infiltrating levels of multiple immune cells and mRNA expression levels of immune checkpoint genes in NSCLC. Furthermore, KAT2B expression was downregulated in tumor tissues, and low KAT2B expression was associated with unsatisfactory efficacy of immune checkpoint blockade (ICB) and poor prognosis of patients with lung adenocarcinoma. Moreover, there were higher somatic genes mutation frequency in patients with low expression of KAT2B. Finally, functional enrichment analysis suggested that KAT2B was mainly linked to the regulation of immune cells and interferon − gamma (IFN-γ) mediated signaling pathways, response to IFN-γ, antigen processing and presentation. Conclusion. This is the first comprehensive study to disclose that KAT2B is correlated with immune infiltrates and may serve as a novel biomarker predicting prognosis and response to immunotherapy in NSCLC.
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Literatur
1.
Zurück zum Zitat Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424CrossRef Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424CrossRef
3.
Zurück zum Zitat Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (2015) Introduction to The 2015 World Health Organization Classification of Tumors of the Lung, Pleura, Thymus, and Heart. J Thorac Oncol 10(9):1240–1242CrossRef Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (2015) Introduction to The 2015 World Health Organization Classification of Tumors of the Lung, Pleura, Thymus, and Heart. J Thorac Oncol 10(9):1240–1242CrossRef
4.
Zurück zum Zitat Howlader N, Forjaz G, Mooradian MJ et al (2020) The Effect of Advances in Lung-Cancer Treatment on Population Mortality. N Engl J Med 383(7):640–649CrossRef Howlader N, Forjaz G, Mooradian MJ et al (2020) The Effect of Advances in Lung-Cancer Treatment on Population Mortality. N Engl J Med 383(7):640–649CrossRef
5.
Zurück zum Zitat Horvath L, Thienpont B, Zhao L, Wolf D, Pircher A (2020) Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook. Mol Cancer 19(1):141CrossRef Horvath L, Thienpont B, Zhao L, Wolf D, Pircher A (2020) Overcoming immunotherapy resistance in non-small cell lung cancer (NSCLC) - novel approaches and future outlook. Mol Cancer 19(1):141CrossRef
6.
Zurück zum Zitat Jenke R, Reßing N, Hansen FK, Aigner A, Büch T (2021) Anticancer therapy with HDAC inhibitors: Mechanism-based combination strategies and future perspectives. Cancers (Basel) 13(4) Jenke R, Reßing N, Hansen FK, Aigner A, Büch T (2021) Anticancer therapy with HDAC inhibitors: Mechanism-based combination strategies and future perspectives. Cancers (Basel) 13(4)
7.
Zurück zum Zitat Liu X, Wang L, Zhao K et al (2008) The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature 451(7180):846–850CrossRef Liu X, Wang L, Zhao K et al (2008) The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature 451(7180):846–850CrossRef
8.
Zurück zum Zitat Liu T, Wang X, Hu W et al (2019) Epigenetically Down-Regulated Acetyltransferase PCAF Increases the Resistance of Colorectal Cancer to 5-Fluorouracil. Neoplasia 21(6):557–570CrossRef Liu T, Wang X, Hu W et al (2019) Epigenetically Down-Regulated Acetyltransferase PCAF Increases the Resistance of Colorectal Cancer to 5-Fluorouracil. Neoplasia 21(6):557–570CrossRef
9.
Zurück zum Zitat Rajendran R, Garva R, Ashour H et al (2013) Acetylation mediated by the p300/CBP-associated factor determines cellular energy metabolic pathways in cancer. Int J Oncol 42(6):1961–1972CrossRef Rajendran R, Garva R, Ashour H et al (2013) Acetylation mediated by the p300/CBP-associated factor determines cellular energy metabolic pathways in cancer. Int J Oncol 42(6):1961–1972CrossRef
10.
Zurück zum Zitat Sulkowski PL, Scanlon SE, Oeck S, Glazer PM (2018) PTEN Regulates Nonhomologous End Joining By Epigenetic Induction of NHEJ1/XLF. Mol Cancer Res 16(8):1241–1254CrossRef Sulkowski PL, Scanlon SE, Oeck S, Glazer PM (2018) PTEN Regulates Nonhomologous End Joining By Epigenetic Induction of NHEJ1/XLF. Mol Cancer Res 16(8):1241–1254CrossRef
11.
Zurück zum Zitat Koutelou E, Farria AT, Dent S (2021) Complex functions of Gcn5 and Pcaf in development and disease. Biochim Biophys Acta Gene Regul Mech. 1864(2): 194609 Koutelou E, Farria AT, Dent S (2021) Complex functions of Gcn5 and Pcaf in development and disease. Biochim Biophys Acta Gene Regul Mech. 1864(2): 194609
12.
Zurück zum Zitat Wang T, Yao W, Shao Y, Zheng R, Huang F (2018) PCAF fine-tunes hepatic metabolic syndrome, inflammatory disease, and cancer. J Cell Mol Med 22(12):5787–5800CrossRef Wang T, Yao W, Shao Y, Zheng R, Huang F (2018) PCAF fine-tunes hepatic metabolic syndrome, inflammatory disease, and cancer. J Cell Mol Med 22(12):5787–5800CrossRef
13.
Zurück zum Zitat Wu Y, Wang X, Xu F et al (2020) The regulation of acetylation and stability of HMGA2 via the HBXIP-activated Akt-PCAF pathway in promotion of esophageal squamous cell carcinoma growth. Nucleic Acids Res 48(9):4858–4876CrossRef Wu Y, Wang X, Xu F et al (2020) The regulation of acetylation and stability of HMGA2 via the HBXIP-activated Akt-PCAF pathway in promotion of esophageal squamous cell carcinoma growth. Nucleic Acids Res 48(9):4858–4876CrossRef
14.
Zurück zum Zitat Hu H, Zhu W, Qin J et al (2017) Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis. Hepatology 65(2):515–528CrossRef Hu H, Zhu W, Qin J et al (2017) Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis. Hepatology 65(2):515–528CrossRef
15.
Zurück zum Zitat Li YH, Li YX, Li M et al (2020) The Ras-ERK1/2 signaling pathway regulates H3K9ac through PCAF to promote the development of pancreatic cancer. Life Sci 256:117936 Li YH, Li YX, Li M et al (2020) The Ras-ERK1/2 signaling pathway regulates H3K9ac through PCAF to promote the development of pancreatic cancer. Life Sci 256:117936
16.
Zurück zum Zitat Wan J, Xu W, Zhan J et al (2016) PCAF-mediated acetylation of transcriptional factor HOXB9 suppresses lung adenocarcinoma progression by targeting oncogenic protein JMJD6. Nucleic Acids Res 44(22):10662–10675CrossRef Wan J, Xu W, Zhan J et al (2016) PCAF-mediated acetylation of transcriptional factor HOXB9 suppresses lung adenocarcinoma progression by targeting oncogenic protein JMJD6. Nucleic Acids Res 44(22):10662–10675CrossRef
17.
Zurück zum Zitat Li T, Fu J, Zeng Z et al (2020) TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res 48(W1):W509–W514 Li T, Fu J, Zeng Z et al (2020) TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res 48(W1):W509–W514
18.
Zurück zum Zitat Ru B, Wong CN, Tong Y et al (2019) TISIDB: an integrated repository portal for tumor-immune system interactions. Bioinformatics 35(20):4200–4202CrossRef Ru B, Wong CN, Tong Y et al (2019) TISIDB: an integrated repository portal for tumor-immune system interactions. Bioinformatics 35(20):4200–4202CrossRef
19.
Zurück zum Zitat Jiang P, Gu S, Pan D et al (2018) Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med 24(10):1550–1558CrossRef Jiang P, Gu S, Pan D et al (2018) Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med 24(10):1550–1558CrossRef
20.
Zurück zum Zitat Rhodes DR, Kalyana-Sundaram S, Mahavisno V et al (2007) Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9(2):166–80 Rhodes DR, Kalyana-Sundaram S, Mahavisno V et al (2007) Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9(2):166–80
21.
Zurück zum Zitat Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45(W1):W98–W102CrossRef Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45(W1):W98–W102CrossRef
22.
Zurück zum Zitat Gao J, Aksoy BA, Dogrusoz U et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1 Gao J, Aksoy BA, Dogrusoz U et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1
23.
Zurück zum Zitat Cerami E, Gao J, Dogrusoz U et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404CrossRef Cerami E, Gao J, Dogrusoz U et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404CrossRef
24.
Zurück zum Zitat Fridman WH, Zitvogel L, Sautès-Fridman C, Kroemer G (2017) The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 14(12):717–734CrossRef Fridman WH, Zitvogel L, Sautès-Fridman C, Kroemer G (2017) The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 14(12):717–734CrossRef
25.
Zurück zum Zitat Azimi F, Scolyer RA, Rumcheva P et al (2012) Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol 30(21):2678–2683CrossRef Azimi F, Scolyer RA, Rumcheva P et al (2012) Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol 30(21):2678–2683CrossRef
26.
Zurück zum Zitat Ingold Heppner B, Untch M, Denkert C et al (2016) Tumor-Infiltrating Lymphocytes: A Predictive and Prognostic Biomarker in Neoadjuvant-Treated HER2-Positive Breast Cancer. Clin Cancer Res 22(23):5747–5754CrossRef Ingold Heppner B, Untch M, Denkert C et al (2016) Tumor-Infiltrating Lymphocytes: A Predictive and Prognostic Biomarker in Neoadjuvant-Treated HER2-Positive Breast Cancer. Clin Cancer Res 22(23):5747–5754CrossRef
27.
Zurück zum Zitat Bagchi S, Yuan R, Engleman EG (2021) Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annu Rev Pathol 16:223–249CrossRef Bagchi S, Yuan R, Engleman EG (2021) Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annu Rev Pathol 16:223–249CrossRef
28.
Zurück zum Zitat Barlesi F, Tomasini P (2020) Non-small-cell lung cancer brain metastases and PD-(L)1 immune checkpoint inhibitors. Lancet Oncol 21(5):607–608CrossRef Barlesi F, Tomasini P (2020) Non-small-cell lung cancer brain metastases and PD-(L)1 immune checkpoint inhibitors. Lancet Oncol 21(5):607–608CrossRef
29.
Zurück zum Zitat Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27(4):450–461CrossRef Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27(4):450–461CrossRef
30.
Zurück zum Zitat Hirsch FR, Suda K, Wiens J, Bunn PA Jr (2016) New and emerging targeted treatments in advanced non-small-cell lung cancer. Lancet 388(10048):1012–1024CrossRef Hirsch FR, Suda K, Wiens J, Bunn PA Jr (2016) New and emerging targeted treatments in advanced non-small-cell lung cancer. Lancet 388(10048):1012–1024CrossRef
31.
Zurück zum Zitat Ettinger DS, Wood DE, Aisner DL et al (2021) NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021. J Natl Compr Canc Netw 19(3):254–266 Ettinger DS, Wood DE, Aisner DL et al (2021) NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021. J Natl Compr Canc Netw 19(3):254–266
32.
Zurück zum Zitat Hellmann MD, Paz-Ares L, Bernabe Caro R et al (2019) Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med 381(21):2020–2031CrossRef Hellmann MD, Paz-Ares L, Bernabe Caro R et al (2019) Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med 381(21):2020–2031CrossRef
33.
Zurück zum Zitat Beatty GL, Gladney WL (2015) Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 21(4):687–692CrossRef Beatty GL, Gladney WL (2015) Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 21(4):687–692CrossRef
34.
Zurück zum Zitat Hu J, Xia X, Zhao Q, Li S (2021) Lysine acetylation of NKG2D ligand Rae-1 stabilizes the protein and sensitizes tumor cells to NKG2D immune surveillance. Cancer Lett 502:143–153CrossRef Hu J, Xia X, Zhao Q, Li S (2021) Lysine acetylation of NKG2D ligand Rae-1 stabilizes the protein and sensitizes tumor cells to NKG2D immune surveillance. Cancer Lett 502:143–153CrossRef
35.
Zurück zum Zitat Hu J, Bernatchez C, Zhang L et al (2017) Induction of NKG2D Ligands on Solid Tumors Requires Tumor-Specific CD8(+) T Cells and Histone Acetyltransferases. Cancer Immunol Res 5(4):300–311CrossRef Hu J, Bernatchez C, Zhang L et al (2017) Induction of NKG2D Ligands on Solid Tumors Requires Tumor-Specific CD8(+) T Cells and Histone Acetyltransferases. Cancer Immunol Res 5(4):300–311CrossRef
36.
Zurück zum Zitat Hu J, Xia X, Gorlick R, Li S (2019) Induction of NKG2D ligand expression on tumor cells by CD8(+) T-cell engagement-mediated activation of nuclear factor-kappa B and p300/CBP-associated factor. Oncogene 38(49):7433–7446CrossRef Hu J, Xia X, Gorlick R, Li S (2019) Induction of NKG2D ligand expression on tumor cells by CD8(+) T-cell engagement-mediated activation of nuclear factor-kappa B and p300/CBP-associated factor. Oncogene 38(49):7433–7446CrossRef
Metadaten
Titel
KAT2B is an immune infiltration-associated biomarker predicting prognosis and response to immunotherapy in non‐small cell lung cancer
verfasst von
Xue Zhou
Ning Wang
Yuefeng Zhang
Hongzhi Yu
Qi Wu
Publikationsdatum
09.09.2021
Verlag
Springer US
Erschienen in
Investigational New Drugs / Ausgabe 1/2022
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-021-01159-6

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