Distinct immune escape and microenvironment between RG-like and pri-OPC-like glioma revealed by single-cell RNA-seq analysis
Weiwei Xian1, Mohammad Asad2, Shuai Wu3, Zhixin Bai1, Fengjiao Li1, Junfeng Lu3, Gaoyu Zu1, Erin Brintnell2, Hong Chen4, Ying Mao5, Guomin Zhou1,6, Bo Liao7, Jinsong Wu3(), Edwin Wang2(), Linya You1,6()
1. Department of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China 2. Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada 3. Glioma Surgery Division, Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China 4. Department of Pathology, Huashan Hospital, Fudan University, Shanghai 200040, China 5. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China 6. Shanghai Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention, Fudan University, Shanghai 200040, China 7. School of Mathematics and Statistics, Hainan Normal University, Haikou 570100, China
The association of neurogenesis and gliogenesis with glioma remains unclear. By conducting single-cell RNA-seq analyses on 26 gliomas, we reported their classification into primitive oligodendrocyte precursor cell (pri-OPC)-like and radial glia (RG)-like tumors and validated it in a public cohort and TCGA glioma. The RG-like tumors exhibited wild-type isocitrate dehydrogenase and tended to carry EGFR mutations, and the pri-OPC-like ones were prone to carrying TP53 mutations. Tumor subclones only in pri-OPC-like tumors showed substantially down-regulated MHC-I genes, suggesting their distinct immune evasion programs. Furthermore, the two subgroups appeared to extensively modulate glioma-infiltrating lymphocytes in distinct manners. Some specific genes not expressed in normal immune cells were found in glioma-infiltrating lymphocytes. For example, glial/glioma stem cell markers OLIG1/PTPRZ1 and B cell-specific receptors IGLC2/IGKC were expressed in pri-OPC-like and RG-like glioma-infiltrating lymphocytes, respectively. Their expression was positively correlated with those of immune checkpoint genes (e.g., LGALS3) and poor survivals as validated by the increased expression of LGALS3 upon IGKC overexpression in Jurkat cells. This finding indicated a potential inhibitory role in tumor-infiltrating lymphocytes and could provide a new way of cancer immune evasion.
DN Louis, A Perry, P Wesseling, DJ Brat, IA Cree, D Figarella-Branger, C Hawkins, HK Ng, SM Pfister, G Reifenberger, R Soffietti, A von Deimling, DW Ellison. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-oncol 2021; 23(8): 1231–1251 https://doi.org/10.1093/neuonc/noab106
2
Genome Atlas Research Network Cancer. et al.. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 2015; 372(26): 2481–2498 https://doi.org/10.1056/NEJMoa1402121
3
BE LaMonica, JH Lui, DV Hansen, AR Kriegstein. Mitotic spindle orientation predicts outer radial glial cell generation in human neocortex. Nat Commun 2013; 4(1): 1665 https://doi.org/10.1038/ncomms2647
W Huang, A Bhaduri, D Velmeshev, S Wang, L Wang, CA Rottkamp, A Alvarez-Buylla, DH Rowitch, AR Kriegstein. Origins and proliferative states of human oligodendrocyte precursor cells. Cell 2020; 182(3): 594–608.e11 https://doi.org/10.1016/j.cell.2020.06.027
H Zong, LF Parada, SJ Baker. Cell of origin for malignant gliomas and its implication in therapeutic development. Cold Spring Harb Perspect Biol 2015; 7(5): a020610 https://doi.org/10.1101/cshperspect.a020610
9
Q Weng, J Wang, J Wang, D He, Z Cheng, F Zhang, R Verma, L Xu, X Dong, Y Liao, X He, A Potter, L Zhang, C Zhao, M Xin, Q Zhou, BJ Aronow, PJ Blackshear, JN Rich, Q He, W Zhou, ML Suvà, RR Waclaw, SS Potter, G Yu, QR Lu. Single-cell transcriptomics uncovers glial progenitor diversity and cell fate determinants during development and gliomagenesis. Cell Stem Cell 2019; 24(5): 707–723.e8 https://doi.org/10.1016/j.stem.2019.03.006
10
H Zong, LF Parada, SJ Baker. Cell of origin for malignant gliomas and its implication in therapeutic development. Cold Spring Harb Perspect Biol 2015; 7(5): a020610 https://doi.org/10.1101/cshperspect.a020610
11
ER Matarredona, N Zarco, C Castro, H Guerrero-Cazares. Editorial: neural stem cells of the subventricular zone: from neurogenesis to glioblastoma origin. Front Oncol 2021; 11: 750116 https://doi.org/10.3389/fonc.2021.750116
12
CP Couturier, S Ayyadhury, PU Le, J Nadaf, J Monlong, G Riva, R Allache, S Baig, X Yan, M Bourgey, C Lee, YCD Wang, V Wee Yong, MC Guiot, H Najafabadi, B Misic, J Antel, G Bourque, J Ragoussis, K Petrecca. Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy. Nat Commun 2020; 11(1): 3406 https://doi.org/10.1038/s41467-020-17186-5
13
C Neftel, J Laffy, MG Filbin, T Hara, ME Shore, GJ Rahme, AR Richman, D Silverbush, MKL Shaw, CM Hebert, J Dewitt, S Gritsch, EM Perez, Castro LN Gonzalez, X Lan, N Druck, C Rodman, D Dionne, A Kaplan, MS Bertalan, J Small, K Pelton, S Becker, D Bonal, QD Nguyen, RL Servis, JM Fung, R Mylvaganam, L Mayr, J Gojo, C Haberler, R Geyeregger, T Czech, I Slavc, BV Nahed, WT Curry, BS Carter, H Wakimoto, PK Brastianos, TT Batchelor, A Stemmer-Rachamimov, M Martinez-Lage, MP Frosch, I Stamenkovic, N Riggi, E Rheinbay, M Monje, O Rozenblatt-Rosen, DP Cahill, AP Patel, T Hunter, IM Verma, KL Ligon, DN Louis, A Regev, BE Bernstein, I Tirosh, ML Suvà. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell 2019; 178(4): 835–849.e21 https://doi.org/10.1016/j.cell.2019.06.024
14
Y Zhang, SA Sloan, LE Clarke, C Caneda, CA Plaza, PD Blumenthal, H Vogel, GK Steinberg, MSB Edwards, G Li, JA III Duncan, SH Cheshier, LM Shuer, EF Chang, GA Grant, MGH Gephart, BA Barres. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 2016; 89(1): 37–53 https://doi.org/10.1016/j.neuron.2015.11.013
15
JE Eckel-Passow, DH Lachance, AM Molinaro, KM Walsh, PA Decker, H Sicotte, M Pekmezci, T Rice, ML Kosel, IV Smirnov, G Sarkar, AA Caron, TM Kollmeyer, CE Praska, AR Chada, C Halder, HM Hansen, LS McCoy, PM Bracci, R Marshall, S Zheng, GF Reis, AR Pico, BP O’Neill, JC Buckner, C Giannini, JT Huse, A Perry, T Tihan, MS Berger, SM Chang, MD Prados, J Wiemels, JK Wiencke, MR Wrensch, RB Jenkins. Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 2015; 372(26): 2499–2508 https://doi.org/10.1056/NEJMoa1407279
16
GW Kim, L Li, M Gorbani, L You, XJ Yang. Mice lacking α-tubulin acetyltransferase 1 are viable but display α-tubulin acetylation deficiency and dentate gyrus distortion. J Biol Chem 2013; 288(28): 20334–20350 https://doi.org/10.1074/jbc.M113.464792
17
MD Young, S Behjati. SoupX removes ambient RNA contamination from droplet-based single-cell RNA sequencing data. Gigascience 2020; 9(12): giaa151 https://doi.org/10.1093/gigascience/giaa151
18
CS McGinnis, LM Murrow, ZJ Gartner. DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors. Cell Syst 2019; 8(4): 329–337.e4 https://doi.org/10.1016/j.cels.2019.03.003
19
AM Newman, CB Steen, CL Liu, AJ Gentles, AA Chaudhuri, F Scherer, MS Khodadoust, MS Esfahani, BA Luca, D Steiner, M Diehn, AA Alizadeh. Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol 2019; 37(7): 773–782 https://doi.org/10.1038/s41587-019-0114-2
VY Kiselev, A Yiu, M Hemberg. scmap: projection of single-cell RNA-seq data across data sets. Nat Methods 2018; 15(5): 359–362 https://doi.org/10.1038/nmeth.4644
22
Manno G La, R Soldatov, A Zeisel, E Braun, H Hochgerner, V Petukhov, K Lidschreiber, ME Kastriti, P Lönnerberg, A Furlan, J Fan, LE Borm, Z Liu, Bruggen D van, J Guo, X He, R Barker, E Sundström, G Castelo-Branco, P Cramer, I Adameyko, S Linnarsson, PV Kharchenko. RNA velocity of single cells. Nature 2018; 560(7719): 494–498 https://doi.org/10.1038/s41586-018-0414-6
MC Vladoiu, I El-Hamamy, LK Donovan, H Farooq, BL Holgado, Y Sundaravadanam, V Ramaswamy, LD Hendrikse, S Kumar, SC Mack, JJY Lee, V Fong, K Juraschka, D Przelicki, A Michealraj, P Skowron, B Luu, H Suzuki, AS Morrissy, FMG Cavalli, L Garzia, C Daniels, X Wu, MA Qazi, SK Singh, JA Chan, MA Marra, D Malkin, P Dirks, L Heisler, T Pugh, K Ng, F Notta, EM Thompson, CL Kleinman, AL Joyner, N Jabado, L Stein, MD Taylor. Childhood cerebellar tumours mirror conserved fetal transcriptional programs. Nature 2019; 572(7767): 67–73 https://doi.org/10.1038/s41586-019-1158-7
25
T Abdelaal, L Michielsen, D Cats, D Hoogduin, H Mei, MJT Reinders, A Mahfouz. A comparison of automatic cell identification methods for single-cell RNA sequencing data. Genome Biol 2019; 20(1): 194 https://doi.org/10.1186/s13059-019-1795-z
26
AS Venteicher, I Tirosh, C Hebert, K Yizhak, C Neftel, MG Filbin, V Hovestadt, LE Escalante, MKL Shaw, C Rodman, SM Gillespie, D Dionne, CC Luo, H Ravichandran, R Mylvaganam, C Mount, ML Onozato, BV Nahed, H Wakimoto, WT Curry, AJ Iafrate, MN Rivera, MP Frosch, TR Golub, PK Brastianos, G Getz, AP Patel, M Monje, DP Cahill, O Rozenblatt-Rosen, DN Louis, BE Bernstein, A Regev, ML Suvà. Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science 2017; 355(6332): eaai8478 https://doi.org/10.1126/science.aai8478
27
CN Henrichsen, E Chaignat, A Reymond. Copy number variants, diseases and gene expression. Hum Mol Genet 2009; 18(R1): R1–R8 https://doi.org/10.1093/hmg/ddp011
28
MV Kuleshov, MR Jones, AD Rouillard, NF Fernandez, Q Duan, Z Wang, S Koplev, SL Jenkins, KM Jagodnik, A Lachmann, MG McDermott, CD Monteiro, GW Gundersen, A Ma’ayan. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 2016; 44(W1): W90–W97 https://doi.org/10.1093/nar/gkw377
29
EY Chen, CM Tan, Y Kou, Q Duan, Z Wang, GV Meirelles, NR Clark, A Ma’ayan. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 2013; 14(1): 128 https://doi.org/10.1186/1471-2105-14-128
30
TL Whiteside. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008; 27(45): 5904–5912 https://doi.org/10.1038/onc.2008.271
31
S Spranger, TF Gajewski. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat Rev Cancer 2018; 18(3): 139–147 https://doi.org/10.1038/nrc.2017.117
32
F Fusella, L Seclì, E Busso, A Krepelova, E Moiso, S Rocca, L Conti, L Annaratone, C Rubinetto, M Mello-Grand, V Singh, G Chiorino, L Silengo, F Altruda, E Turco, A Morotti, S Oliviero, I Castellano, F Cavallo, P Provero, G Tarone, M Brancaccio. The IKK/NF-κB signaling pathway requires Morgana to drive breast cancer metastasis. Nat Commun 2017; 8(1): 1636 https://doi.org/10.1038/s41467-017-01829-1
33
J Kitayama, H Nagawa, H Yasuhara, N Tsuno, W Kimura, Y Shibata, T Muto. Suppressive effect of basic fibroblast growth factor on transendothelial emigration of CD4+ T-lymphocyte. Cancer Res 1994; 54(17): 4729–4733
34
T Yaguchi, H Sumimoto, C Kudo-Saito, N Tsukamoto, R Ueda, T Iwata-Kajihara, H Nishio, N Kawamura, Y Kawakami. The mechanisms of cancer immunoescape and development of overcoming strategies. Int J Hematol 2011; 93(3): 294–300 https://doi.org/10.1007/s12185-011-0799-6
35
S Spranger, TF Gajewski. A new paradigm for tumor immune escape: β-catenin-driven immune exclusion. J Immunother Cancer 2015; 3(1): 43 https://doi.org/10.1186/s40425-015-0089-6
36
JJ Luke, R Bao, RF Sweis, S Spranger, TF Gajewski. WNT/β-catenin pathway activation correlates with immune exclusion across human cancers. Clin Cancer Res 2019; 25(10): 3074–3083 https://doi.org/10.1158/1078-0432.CCR-18-1942
37
D Swafford, S Manicassamy. Wnt signaling in dendritic cells: its role in regulation of immunity and tolerance. Discov Med 2015; 19(105): 303–310
38
P Kaler, L Augenlicht, L Klampfer. Activating mutations in β-catenin in colon cancer cells alter their interaction with macrophages; the role of snail. PLoS One 2012; 7(9): e45462 https://doi.org/10.1371/journal.pone.0045462
39
G Guo, M Yu, W Xiao, E Celis, Y Cui. Local activation of p53 in the tumor microenvironment overcomes immune suppression and enhances antitumor immunity. Cancer Res 2017; 77(9): 2292–2305 https://doi.org/10.1158/0008-5472.CAN-16-2832
40
K Sabapathy, SY Nam. Defective MHC class I antigen surface expression promotes cellular survival through elevated ER stress and modulation of p53 function. Cell Death Differ 2008; 15(9): 1364–1374 https://doi.org/10.1038/cdd.2008.55
41
M Ghosh, S Saha, J Bettke, R Nagar, A Parrales, T Iwakuma. Mutant p53 aids cancer cells in evading lethal innate immune responses. Cancer Discov 2021; 11(5): OF14 https://doi.org/10.1158/2159-8290.CD-RW2021-022
42
A Garancher, H Suzuki, S Haricharan, LQ Chau, MB Masihi, JM Rusert, PS Norris, F Carrette, MM Romero, SA Morrissy, P Skowron, FMG Cavalli, H Farooq, V Ramaswamy, SJM Jones, RA Moore, AJ Mungall, Y Ma, N Thiessen, Y Li, A Morcavallo, L Qi, M Kogiso, Y Du, P Baxter, JJ Henderson, JR Crawford, ML Levy, JM Olson, YJ Cho, AJ Deshpande, XN Li, L Chesler, MA Marra, H Wajant, OJ Becher, LM Bradley, CF Ware, MD Taylor, RJ Wechsler-Reya. Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma. Nat Neurosci 2020; 23(7): 842–853 https://doi.org/10.1038/s41593-020-0628-4
ME Hegi, AC Diserens, T Gorlia, MF Hamou, N de Tribolet, M Weller, JM Kros, JA Hainfellner, W Mason, L Mariani, JEC Bromberg, P Hau, RO Mirimanoff, JG Cairncross, RC Janzer, R Stupp. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352(10): 997–1003 https://doi.org/10.1056/NEJMoa043331
AR Pombo Antunes, I Scheyltjens, J Duerinck, B Neyns, K Movahedi, JA Van Ginderachter. Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies. Elife 2020; 9: e52176 https://doi.org/10.7554/eLife.52176
47
M Martinez-Lage, TM Lynch, Y Bi, C Cocito, GP Way, S Pal, J Haller, RE Yan, A Ziober, A Nguyen, M Kandpal, DM O’Rourke, JP Greenfield, CS Greene, RV Davuluri, N Dahmane. Immune landscapes associated with different glioblastoma molecular subtypes. Acta Neuropathol Commun 2019; 7: 203 https://doi.org/10.1186/s40478-019-0803-6
48
P Nieto, M Elosua-Bayes, JL Trincado, D Marchese, R Massoni-Badosa, M Salvany, A Henriques, J Nieto, S Aguilar-Fernández, E Mereu, C Moutinho, S Ruiz, P Lorden, VT Chin, D Kaczorowski, CL Chan, R Gallagher, A Chou, E Planas-Rigol, C Rubio-Perez, I Gut, JM Piulats, J Seoane, JE Powell, E Batlle, H Heyn. A single-cell tumor immune atlas for precision oncology. Genome Res 2021; 31(10): 1913–1926 https://doi.org/10.1101/gr.273300.120
49
J Dai, KK Bercury, JT Ahrendsen, WB Macklin. Olig1 function is required for oligodendrocyte differentiation in the mouse brain. J Neurosci 2015; 35(10): 4386–4402 https://doi.org/10.1523/JNEUROSCI.4962-14.2015
ML Suvà, E Rheinbay, SM Gillespie, AP Patel, H Wakimoto, SD Rabkin, N Riggi, AS Chi, DP Cahill, BV Nahed, WT Curry, RL Martuza, MN Rivera, N Rossetti, S Kasif, S Beik, S Kadri, I Tirosh, I Wortman, AK Shalek, O Rozenblatt-Rosen, A Regev, DN Louis, BE Bernstein. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 2014; 157(3): 580–594 https://doi.org/10.1016/j.cell.2014.02.030
52
AP Patel, I Tirosh, JJ Trombetta, AK Shalek, SM Gillespie, H Wakimoto, DP Cahill, BV Nahed, WT Curry, RL Martuza, DN Louis, O Rozenblatt-Rosen, ML Suvà, A Regev, BE Bernstein. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 2014; 344(6190): 1396–1401 https://doi.org/10.1126/science.1254257
T Kouo, L Huang, AB Pucsek, M Cao, S Solt, T Armstrong, E Jaffee. Galectin-3 shapes antitumor immune responses by suppressing CD8 T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol Res 2015; 3(4): 412–423 https://doi.org/10.1158/2326-6066.CIR-14-0150
C Bottino, R Castriconi, D Pende, P Rivera, M Nanni, B Carnemolla, C Cantoni, J Grassi, S Marcenaro, N Reymond, M Vitale, L Moretta, M Lopez, A Moretta. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med 2003; 198(4): 557–567 https://doi.org/10.1084/jem.20030788
57
WM Hu, YZ Yang, TZ Zhang, CF Qin, XN Li. LGALS3 is a poor prognostic factor in diffusely infiltrating gliomas and is closely correlated with CD163+ tumor-associated macrophages. Front Med (Lausanne) 2020; 7: 182 https://doi.org/10.3389/fmed.2020.00182
58
DG Song, Q Ye, M Poussin, GM Harms, M Figini, DJ Jr Powell. CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. Blood 2012; 119(3): 696–706 https://doi.org/10.1182/blood-2011-03-344275
59
EY Chiang, PE Almeida, DE Almeida Nagata, KH Bowles, X Du, AS Chitre, KL Banta, Y Kwon, B McKenzie, S Mittman, R Cubas, KR Anderson, S Warming, JL Grogan. CD96 functions as a co-stimulatory receptor to enhance CD8+ T cell activation and effector responses. Eur J Immunol 2020; 50(6): 891–902 https://doi.org/10.1002/eji.201948405
60
K Pfistershammer, O Majdic, J Stöckl, G Zlabinger, S Kirchberger, P Steinberger, W Knapp. CD63 as an activation-linked T cell costimulatory element. J Immunol 2004; 173(10): 6000–6008 https://doi.org/10.4049/jimmunol.173.10.6000
61
SS Yoon, HJ Kim, DH Chung, TJ Kim. CD99 costimulation up-regulates T cell receptor-mediated activation of JNK and AP-1. Mol Cells 2004; 18(2): 186–191
62
C Zhu, D Mustafa, P Zheng, M van der Weiden, A Sacchetti, M Brandt, I Chrifi, D Tempel, PJM Leenen, DJ Duncker, C Cheng, JM Kros. Activation of CECR1 in M2-like TAMs promotes paracrine stimulation-mediated glial tumor progression. Neuro-oncol 2017; 19(5): 648–659 https://doi.org/10.1093/neuonc/now251
63
AS Berghoff, B Kiesel, G Widhalm, D Wilhelm, O Rajky, S Kurscheid, P Kresl, A Wöhrer, C Marosi, ME Hegi, M Preusser. Correlation of immune phenotype with IDH mutation in diffuse glioma. Neuro-oncol 2017; 19(11): 1460–1468 https://doi.org/10.1093/neuonc/nox054
64
M Campoli, S Ferrone. HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance. Oncogene 2008; 27(45): 5869–5885 https://doi.org/10.1038/onc.2008.273
65
N McGranahan, R Rosenthal, CT Hiley, AJ Rowan, TBK Watkins, GA Wilson, NJ Birkbak, S Veeriah, Loo P Van, J Herrero, C; TRACERx Consortium Swanton. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 2017; 171(6): 1259–1271.e11 https://doi.org/10.1016/j.cell.2017.10.001
66
M Silginer, S Nagy, C Happold, H Schneider, M Weller, P Roth. Autocrine activation of the IFN signaling pathway may promote immune escape in glioblastoma. Neuro-oncol 2017; 19(10): 1338–1349 https://doi.org/10.1093/neuonc/nox051
67
H Suzuki, K Aoki, K Chiba, Y Sato, Y Shiozawa, Y Shiraishi, T Shimamura, A Niida, K Motomura, F Ohka, T Yamamoto, K Tanahashi, M Ranjit, T Wakabayashi, T Yoshizato, K Kataoka, K Yoshida, Y Nagata, A Sato-Otsubo, H Tanaka, M Sanada, Y Kondo, H Nakamura, M Mizoguchi, T Abe, Y Muragaki, R Watanabe, I Ito, S Miyano, A Natsume, S Ogawa. Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet 2015; 47(5): 458–468 https://doi.org/10.1038/ng.3273
68
CW Brennan, RG Verhaak, A McKenna, B Campos, H Noushmehr, SR Salama, S Zheng, D Chakravarty, JZ Sanborn, SH Berman, R Beroukhim, B Bernard, CJ Wu, G Genovese, I Shmulevich, J Barnholtz-Sloan, L Zou, R Vegesna, SA Shukla, G Ciriello, WK Yung, W Zhang, C Sougnez, T Mikkelsen, K Aldape, DD Bigner, Meir EG Van, M Prados, A Sloan, KL Black, J Eschbacher, G Finocchiaro, W Friedman, DW Andrews, A Guha, M Iacocca, BP O'Neill, G Foltz, J Myers, DJ Weisenberger, R Penny, R Kucherlapati, CM Perou, DN Hayes, R Gibbs, M Marra, GB Mills, E Lander, P Spellman, R Wilson, C Sander, J Weinstein, M Meyerson, S Gabriel, PW Laird, D Haussler, G Getz, L; TCGA Research Network Chin. The somatic genomic landscape of glioblastoma. Cell 2013; 155(2): 462–477 https://doi.org/10.1016/j.cell.2013.09.034
C Zhang, LM Moore, X Li, WKA Yung, W Zhang. IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma. Neuro-oncol 2013; 15(9): 1114–1126 https://doi.org/10.1093/neuonc/not087
71
R Ahmed, Z Omidian, A Giwa, B Cornwell, N Majety, DR Bell, S Lee, H Zhang, A Michels, S Desiderio, S Sadegh-Nasseri, H Rabb, S Gritsch, ML Suva, P Cahan, R Zhou, C Jie, T Donner, ARA Hamad. A public BCR present in a unique dual-receptor-expressing lymphocyte from type 1 Diabetes Patients Encodes a Potent T Cell Autoantigen. Cell 2019; 177(6): 1583–1599.e16 https://doi.org/10.1016/j.cell.2019.05.007
72
AS Japp, W Meng, AM Rosenfeld, DJ Perry, P Thirawatananond, RL Bacher, C Liu, JS Gardner, MA Atkinson, KH Kaestner, TM Brusko, A Naji, ET Luning Prak, MR Betts. TCR+/BCR+ dual-expressing cells and their associated public BCR clonotype are not enriched in type 1 diabetes. Cell 2021; 184(3): 827–839.e14 https://doi.org/10.1016/j.cell.2020.11.035
73
Y Liu, EG Shepherd, LD Nelin. MAPK phosphatases—regulating the immune response. Nat Rev Immunol 2007; 7(3): 202–212 https://doi.org/10.1038/nri2035
