Full text
3/2026
vol. 64
Original paper
Immune phenotype-guided signature reveals tumor immune microenvironment, intratumoral heterogeneity, TCR Shannon diversity, genome instability and immunotherapy sensitivity of glioma
Department of Thoracic Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
Departments of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Departments of Neurosurgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
Folia Neuropathol 2026; 64 (3): 240-274
Data publikacji online: 2026/10/23
- Aran D, Hu Z, Butte AJ. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol 2017; 18: 220.
- Behan FM, Iorio F, Picco G, Gonçalves E, Beaver CM, Migliardi G, Santos R, Rao Y, Sassi F, Pinnelli M, Ansari R, Harper S, Jack- son DA, McRae R, Pooley R, Wilkinson P, van der Meer D, Dow D, Buser-Doepner C, Bertotti A, Trusolino L, Stronach EA, Saez- Rodriguez J, Yusa K, Garnett MJ. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 2019; 568: 511-516.
- Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 1995; 57: 289-300.
- Berghoff AS, Kiesel B, Widhalm G, Wilhelm D, Rajky O, Kurs-cheid S, Kresl P, Wöhrer A, Marosi C, Hegi ME, Preusser M. Correlation of immune phenotype with IDH mutation in diffuse glioma. Neuro Oncol 2017; 19: 1460-1468.
- Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, Laird PW, Onofrio RC, Winckler W, Weir BA, Beroukhim R, Pellman D, Levine DA, Lander ES, Meyerson M, Getz G. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol 2012; 30: 413-421.
- Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, Gouw AM, Baylot V, Gütgemann I, Eilers M, Felsher DW. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 2016; 352: 227-231.
- Chandramohan V, Bao X, Yu X, Parker S, McDowall C, Yu YR, Healy P, Desjardins A, Gunn MD, Gromeier M, Nair SK, Pastan IH, Bigner DD. Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations. J Immunother Cancer 2019; 7: 142.
- Charoentong P, Finotello F, Angelova M, Mayer C, Efremova M, Rieder D, Hackl H, Trajanoski Z. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep 2017; 18: 248-262.
- Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, Sher X, Liu XQ, Lu H, Nebozhyn M, Zhang C, Lunceford JK, Joe A, Cheng J, Webber AL, Ibrahim N, Plimack ER, Ott PA, Seiwert TY, Ribas A, McClanahan TK, Tomassini JE, Loboda A, Kaufman D. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 2018; 362: eaar3593.
- Daniel P, Sabri S, Chaddad A, Meehan B, Jean-Claude B, Rak J, Abdulkarim BS. Temozolomide induced hypermutation in glioma: evolutionary mechanisms and therapeutic opportunities. Front Oncol 2019; 9: 41.
- Friedman JH. Greedy function approximation: a gradient boosting machine. Ann Stat 2001; 29: 1189-1232.
- Gautier L, Cope L, Bolstad BM, Irizarry RA. affy--analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 2004; 20: 307-315.
- Goeman JJ. L1 penalized estimation in the Cox proportional hazards model. Biom J 2010; 52: 70-84.
- Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, McCracken MN, Gupta R, Tsai JM, Sinha R, Corey D, Ring AM, Connolly AJ, Weissman IL. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 2017; 545: 495-499.
- Greter M, Heppner FL, Lemos MP, Odermatt BM, Goebels N, Laufer T, Noelle RJ, Becher B. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 2005; 11: 328-334.
- Gromeier M, Brown MC, Zhang G, Lin X, Chen Y, Wei Z, Beaubier N, Yan H, He Y, Desjardins A, Herndon JE, 2nd, Varn FS, Verhaak RG, Zhao J, Bolognesi DP, Friedman AH, Friedman HS, McSherry F, Muscat AM, Lipp ES, Nair SK, Khasraw M, Peters KB, Randazzo D, Sampson JH, McLendon RE, Bigner DD, Ashley DM. Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy. Nat Commun 2021; 12: 352.
- Hänzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-Seq data. BMC Bioinformatics 2013; 14: 7.
- Hazra A, Gogtay N. Biostatistics series module 3: comparing groups: numerical variables. Indian J Dermatol 2016; 61: 251-260.
- He Y, Jiang Z, Chen C, Wang X. Classification of triple-negative breast cancers based on Immunogenomic profiling. J Exp Clin Cancer Res 2018; 37: 327.
- Horvath S, Zhang B, Carlson M, Lu KV, Zhu S, Felciano RM, Laurance MF, Zhao W, Qi S, Chen Z, Lee Y, Scheck AC, Liau LM, Wu H, Geschwind DH, Febbo PG, Kornblum HI, Cloughesy TF, Nelson SF, Mischel PS. Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target. Proc Natl Acad Sci USA 2006; 103: 17402-17407.
- Hu J. Automated detection of driver fatigue based on AdaBoost classifier with EEG signals. Front Comput Neurosci 2017; 11: 72.
- Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, Berent-Maoz B, Pang J, Chmielowski B, Cherry G, Seja E, Lomeli S, Kong X, Kelley MC, Sosman JA, Johnson DB, Ribas A, Lo RS. Genomic and transcriptomic features of response to Anti-PD-1 therapy in metastatic melanoma. Cell 2016; 165: 35-44.
- Jiang T, Mao Y, Ma W, Mao Q, You Y, Yang X, Jiang C, Kang C, Li X, Chen L, Qiu X, Wang W, Li W, Yao Y, Li S, Li S, Wu A, Sai K, Bai H, Li G, Chen B, Yao K, Wei X, Liu X, Zhang Z, Dai Y, Lv S, Wang L, Lin Z, Dong J, Xu G, Ma X, Cai J, Zhang W, Wang H, Chen L, Zhang C, Yang P, Yan W, Liu Z, Hu H, Chen J, Liu Y, Yang Y, Wang Z, Wang Z, Wang Y, You G, Han L, Bao Z, Liu Y, Wang Y, Fan X, Liu S, Liu X, Wang Y, Wang Q. CGCG clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 2016; 375: 263-273.
- Jiang Z, Liu Z, Li M, Chen C, Wang X. Immunogenomics analysis reveals that TP53 mutations inhibit tumor immunity in gastric cancer. Transl Oncol 2018; 11: 1171-1187.
- Khasraw M, Walsh KM, Heimberger AB, Ashley DM. What is the burden of proof for tumor mutational burden in gliomas? Neuro Oncol 2020; 23: 17-22.
- Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 2008; 9: 559.
- Lauss M, Donia M, Harbst K, Andersen R, Mitra S, Rosengren F, Salim M, Vallon-Christersson J, Törngren T, Kvist A, Ringnér M, Svane IM, Jönsson G. Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma. Nat Commun 2017; 8: 1738.
- Li B, Severson E, Pignon JC, Zhao H, Li T, Novak J, Jiang P, Shen H, Aster JC, Rodig S, Signoretti S, Liu JS, Liu XS. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol 2016; 17: 174.
- Lim M, Weller M, Idbaih A, Steinbach J, Finocchiaro G, Raval RR, Ansstas G, Baehring J, Taylor JW, Honnorat J, Petrecca K, De Vos F, Wick A, Sumrall A, Sahebjam S, Mellinghoff IK, Kinoshita M, Roberts M, Slepetis R, Warad D, Leung D, Lee M, Reardon DA, Omuro A. Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. Neuro Oncol 2022; 24: 1935-1949.
- Lim M, Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol 2018; 15: 422-442.
- Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature 2015; 523: 337-341.
- Lyu H, Li M, Jiang Z, Liu Z, Wang X. Correlate the TP53 mutation and the HRAS mutation with immune signatures in head and neck squamous cell cancer. Comput Struct Biotechnol J 2019; 17: 1020-1030.
- Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE, III, Koeppen H, Astarita JL, Cubas R, Jhunjhunwala S, Banchereau R, Yang Y, Guan Y, Chalouni C, Ziai J, Şenbabaoğlu Y, Santoro S, Sheinson D, Hung J, Giltnane JM, Pierce AA, Mesh K, Lianoglou S, Riegler J, Carano RAD, Eriksson P, Höglund M, Somarriba L, Halligan DL, van der Heijden MS, Loriot Y, Rosenberg JE, Fong L, Mellman I, Chen DS, Green M, Derleth C, Fine GD, Hegde PS, Bourgon R, Powles T. TGFβ attenuates tumour re- sponse to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018; 554: 544-548.
- McGrail DJ, Pilié PG, Rashid NU, Voorwerk L, Slagter M, Kok M, Jonasch E, Khasraw M, Heimberger AB, Lim B, Ueno NT, Litton JK, Ferrarotto R, Chang JT, Moulder SL, Lin SY. High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol 2021; 32: 661-672.
- Monti S, Tamayo P, Mesirov J, Golub T. Consensus clustering: a resampling-based method for class discovery and visualization of gene expression microarray data. Mach Learn 2003; 52: 91-118.
- Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Ho- ang CD, Diehn M, Alizadeh AA. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods 2015; 12: 453-457.
- Nishino M, Ramaiya NH, Hatabu H, Hodi FS. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat Rev Clin Oncol 2017; 14: 655-668.
- Ogunleye A, Wang QG. XGBoost model for chronic kidney disease diagnosis. IEEE/ACM Trans Comput Biol Bioinform 2020; 17: 2131-2140.
- Omuro A, Brandes AA, Carpentier AF, Idbaih A, Reardon DA, Cloughesy T, Sumrall A, Baehring J, van den Bent M, Bähr O, Lombardi G, Mulholland P, Tabatabai G, Lassen U, Sepulveda JM, Khasraw M, Vauleon E, Muragaki Y, Di Giacomo AM, Butow-ski N, Roth P, Qian X, Fu AZ, Liu Y, Potter V, Chalamandaris AG, Tatsuoka K, Lim M, Weller M. Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: an international randomized phase 3 trial. Neuro Oncol 2023; 25: 123-134.
- Panda A, Mehnert JM, Hirshfield KM, Riedlinger G, Damare S, Saunders T, Kane M, Sokol L, Stein MN, Poplin E, Rodriguez- Rodriguez L, Silk AW, Aisner J, Chan N, Malhotra J, Frankel M, Kaufman HL, Ali S, Ross JS, White EP, Bhanot G, Ganesan S. Immune activation and benefit from avelumab in EBV-positive gastric cancer. J Natl Cancer Inst 2018; 110: 316-320.
- Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 2007; 13: 84-88.
- Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, Sun Y, Zhao E, Vatan L, Szeliga W, Kotarski J, Tarkowski R, Dou Y, Cho K, Hensley-Alford S, Munkarah A, Liu R, Zou W. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 2015; 527: 249-253.
- Pombo Antunes AR, Scheyltjens I, Duerinck J, Neyns B, Movahedi K, Van Ginderachter JA. Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies. Elife 2020; 9: e52176.
- Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, Baehring J, Ahluwalia MS, Roth P, Bähr O, Phuphanich S, Sepulveda JM, De Souza P, Sahebjam S, Carleton M, Tatsuoka K, Taitt C, Zwirtes R, Sampson J, Weller M. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the CheckMate 143 phase 3 randomized clinical trial. JAMA Oncol 2020; 6: 1003-1010.
- Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, Müller M. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 2011; 12: 77.
- Rodrigues JC, Gonzalez GC, Zhang L, Ibrahim G, Kelly JJ, Gustafson MP, Lin Y, Dietz AB, Forsyth PA, Yong VW, Parney IF. Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol 2009; 12: 351-365.
- Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O’Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387: 1909-1920.
- Saha D, Martuza RL, Rabkin SD. Macrophage polarization contributes to glioblastoma eradication by combination immunovirotherapy and immune checkpoint blockade. Cancer Cell 2017; 32: 253-267.e255.
- Sejda A, Grajkowska W, Trubicka J, Szutowicz E, Wojdacz T, Kloc W, Iżycka-Świeszewska E. WHO CNS5 2021 classification of gliomas: a practical review and road signs for diagnosing pathologists and proper patho-clinical and neuro-oncological cooperation. Folia Neuropathol 2022; 60: 137-152.
- Şenbabaoğlu Y, Gejman RS, Winer AG, Liu M, Van Allen EM, de Velasco G, Miao D, Ostrovnaya I, Drill E, Luna A, Weinhold N, Lee W, Manley BJ, Khalil DN, Kaffenberger SD, Chen Y, Danilova L, Voss MH, Coleman JA, Russo P, Reuter VE, Chan TA, Cheng EH, Scheinberg DA, Li MO, Choueiri TK, Hsieh JJ, Sander C, Hakimi AA. Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures. Genome Biol 2016; 17: 231.
- Siegel RL, Miller K D, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2020. CA Cancer J Clin 2020; 70: 145-164.
- Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J, Nordgren H, Farmer P, Praz V, Haibe-Kains B, Desmedt C, Larsimont D, Cardoso F, Peterse H, Nuyten D, Buyse M, Van de Vijver MJ, Bergh J, Piccart M, Delorenzi M. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst 2006; 98: 262-272.
- Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005; 102: 15545-15550.
- Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, Sevillano M, Ibiza S, Cañellas A, Hernando-Momblona X, Byrom D, Matarin JA, Calon A, Rivas EI, Nebreda AR, Riera A, Attolini CS, Batlle E. TGFb drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018; 554: 538-543.
- Taylor AM, Shih J, Ha G, Gao GF, Zhang X, Berger AC, Schumacher SE, Wang C, Hu H, Liu J, Lazar AJ, Cherniack AD, Beroukhim R, Meyerson M. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell 2018; 33: 676-689.e3.
- Tibshirani R. The lasso method for variable selection in the Cox model. Stat Med 1997; 16: 385-395.
- Ulloa-Montoya F, Louahed J, Dizier B, Gruselle O, Spiessens B, Lehmann FF, Suciu S, Kruit WH, Eggermont AM, Vansteenkiste J, Brichard VG. Predictive gene signature in MAGE-A3 antigen- specific cancer immunotherapy. J Clin Oncol 2013; 31: 2388-2395.
- Verhaak RG, Tamayo P, Yang JY, Hubbard D, Zhang H, Creighton CJ, Fereday S, Lawrence M, Carter SL, Mermel CH, Kostic AD, Etemadmoghadam D, Saksena G, Cibulskis K, Duraisamy S, Levanon K, Sougnez C, Tsherniak A, Gomez S, Onofrio R, Gabriel S, Chin L, Zhang N, Spellman PT, Zhang Y, Akbani R, Hoadley KA, Kahn A, Kobel M, Huntsman D, Soslow RA, Defazio A, Birrer MJ, Gray JW, Weinstein JN, Bowtell DD, Drapkin R, Mesirov JP, Getz G, Levine DA, Meyerson M. Prognostically relevant gene signatures of high-grade serous ovarian carcinoma. J Clin Invest 2013; 123: 517-525.
- Vickers AJ, Elkin EB. Decision curve analysis: a novel method for evaluating prediction models. Med Decis Making 2006; 26: 565-574.
- Voron T, Marcheteau E, Pernot S, Colussi O, Tartour E, Taieb J, Terme M. Control of the immune response by pro-angiogenic factors. Front Oncol 2014; 4: 70.
- Wagner GP, Kin K, Lynch VJ. Measurement of mRNA abundance using RNA-seq data: RPKM measure is inconsistent among samples. Theory in biosci 2012; 131: 281-285.
- Wiendl H, Mitsdoerffer M, Hofmeister V, Wischhusen J, Bornemann A, Meyermann R, Weiss EH, Melms A, Weller M. A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape. J Immunol 2002; 168: 4772-4780.
- Yang J, Zhang D, Frangi AF, Yang JY. Two-dimensional PCA: a new approach to appearance-based face representation and recognition. IEEE TransPattern Anal Mach Intell 2004; 26: 131-137.
- Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W, Trevino V, Shen H, Laird PW, Levine DA, Carter SL, Getz G, Stemke-Hale K, Mills GB, Verhaak RG. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun 2013; 4: 2612.
- Zeng D, Ye Z, Shen R, Yu G, Wu J, Xiong Y, Zhou R, Qiu W, Huang N, Sun L, Li X, Bin J, Liao Y, Shi M, Liao W. IOBR: multi-omics immuno-oncology biological research to decode tumor microenvironment and signatures. Front Immunol 2021; 12: 687975.
- Zhao B, Wang Y, Wang Y, Dai C, Wang Y, Ma W. Investigation of genetic determinants of glioma immune phenotype by integrative immunogenomic scale analysis. Front Immunol 2021; 12: 557994.
Copyright: © 2026 Mossakowski Medical Research Centre Polish Academy of Sciences and the Polish Association of Neuropathologists. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.