CD8+T cell-based molecular subtypes with heterogeneous immune landscapes and clinical significance in acute myeloid leukemia

被引:3
作者
Zhong, Fangmin [1 ]
Yao, Fangyi [1 ]
Jiang, Junyao [1 ]
Yu, Xiajing [1 ]
Liu, Jing [1 ]
Huang, Bo [1 ]
Wang, Xiaozhong [1 ]
机构
[1] Nanchang Univ, Affiliated Hosp 2, Jiangxi Prov Clin Res Ctr Lab Med,Jiangxi Med Coll, Dept Clin Lab,Jiangxi Prov Key Lab Lab Med, Nanchang, Jiangxi, Peoples R China
基金
中国国家自然科学基金;
关键词
CD8+T cells; Molecular subtypes; Machine learning; Immunotherapy; Acute myeloid leukemia; REGULATORY T-CELLS;
D O I
10.1007/s00011-023-01839-4
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
BackgroundAcute myeloid leukemia (AML) is a heterogeneous hematological malignancy. Although high-dose chemotherapy is the primary treatment option, it cannot cure the disease, and new approaches need to be developed. The tumor microenvironment (TME) plays a crucial role in tumor biology and immunotherapy. CD8 + T cells are the main anti-tumor immune effector cells, and it is essential to understand their relationship with the TME and the clinicopathological characteristics of AML.MethodsIn this study, we conducted a systematic analysis of CD8 + T cell infiltration through multi-omics data and identified molecular subtypes with significant differences in CD8 + T cell infiltration and prognosis. We aimed to provide a comprehensive evaluation of the pathological factors affecting the prognosis of AML patients and to offer theoretical support for the precise treatment of AML.ResultsOur results indicate that CD8 + T cell infiltration is accompanied by immunosuppression, and that there are two molecular subtypes, with the C2 subtype having a significantly worse prognosis than the C1 subtype, as well as less CD8 + T cell infiltration. We developed a signature to distinguish molecular subtypes using multiple machine learning algorithms and validated the prognostic predictive power of molecular subtypes in nine AML cohorts including 2059 AML patients. Our findings suggest that there are different immunosuppressive characteristics between the two subtypes. The C1 subtype has up-regulated expression of immune checkpoints such as CTLA4, PD-1, LAG3, and TIGITD, while the C2 subtype infiltrates more immunosuppressive cells such as Tregs and M2 macrophages. The C1 subtype is more responsive to anti-PD-1 immunotherapy and induction chemotherapy, as well as having higher immune and cancer-promoting variant-related pathway activity. Patients with the C2 subtype had a higher FLT3 mutation rate, higher WBC counts, and a higher percentage of blasts, as indicated by increased activity of signaling pathways involved in energy metabolism and cell proliferation. Analysis of data from ex vivo AML cell drug assays has identified a group of drugs that differ in therapeutic sensitivity between molecular subtypes.ConclusionsOur results suggest that the molecular subtypes we constructed have potential application value in the prognosis evaluation and treatment guidance of AML patients.
引用
收藏
页码:329 / 344
页数:16
相关论文
共 39 条
[11]  
Horowitz M M, 1990, Blood, V75, P555
[12]   Bone marrow CD8 T cells express high frequency of PD-1 and exhibit reduced anti-leukemia response in newly diagnosed AML patients [J].
Jia, Bei ;
Wang, Liru ;
Claxton, David F. ;
Ehmann, W. Christopher ;
Rybka, Witold B. ;
Mineishi, Shin ;
Rizvi, Syed ;
Shike, Hiroko ;
Bayerl, Michael ;
Schell, Todd D. ;
Hohl, Raymond J. ;
Zheng, Hong .
BLOOD CANCER JOURNAL, 2018, 8
[13]   Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response [J].
Jiang, Peng ;
Gu, Shengqing ;
Pan, Deng ;
Fu, Jingxin ;
Sahu, Avinash ;
Hu, Xihao ;
Li, Ziyi ;
Traugh, Nicole ;
Bu, Xia ;
Li, Bo ;
Liu, Jun ;
Freeman, Gordon J. ;
Brown, Myles A. ;
Wucherpfennig, Kai W. ;
Liu, X. Shirley .
NATURE MEDICINE, 2018, 24 (10) :1550-+
[14]   Molecular Minimal Residual Disease in Acute Myeloid Leukemia [J].
Jongen-Lavrencic, M. ;
Grob, T. ;
Hanekamp, D. ;
Kavelaars, F. G. ;
al Hinai, A. ;
Zeilemaker, A. ;
Erpelinck-Verschueren, C. A. J. ;
Gradowska, P. L. ;
Meijer, R. ;
Cloos, J. ;
Biemond, B. J. ;
Graux, C. ;
Kooy, M. van Marwijk ;
Manz, M. G. ;
Pabst, T. ;
Passweg, J. R. ;
Havelange, V. ;
Ossenkoppele, G. J. ;
Sanders, M. A. ;
Schuurhuis, G. J. ;
Lowenberg, B. ;
Valk, P. J. M. .
NEW ENGLAND JOURNAL OF MEDICINE, 2018, 378 (13) :1189-1199
[15]   Acute myeloid leukemia: current progress and future directions [J].
Kantarjian, Hagop ;
Kadia, Tapan ;
DiNardo, Courtney ;
Daver, Naval ;
Borthakur, Gautam ;
Jabbour, Elias ;
Garcia-Manero, Guillermo ;
Konopleva, Marina ;
Ravandi, Farhad .
BLOOD CANCER JOURNAL, 2021, 11 (02)
[16]   Updates on targeted therapies for acute myeloid leukaemia [J].
Kayser, Sabine ;
Levis, Mark J. .
BRITISH JOURNAL OF HAEMATOLOGY, 2022, 196 (02) :316-328
[17]   Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy [J].
Knaus, Hanna A. ;
Berglund, Sofia ;
Hackl, Hubert ;
Blackford, Amanda L. ;
Zeidner, Joshua F. ;
Montiel-Esparza, Rail ;
Mukhopadhyay, Rupkatha ;
Vanura, Katrina ;
Blazar, Bruce R. ;
Karp, Judith E. ;
Luznik, Leo ;
Gojo, Ivana .
JCI INSIGHT, 2018, 3 (21)
[18]   CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330 [J].
Krupka, Christina ;
Kufer, Peter ;
Kischel, Roman ;
Zugmaier, Gerhard ;
Boegeholz, Jan ;
Koehnke, Thomas ;
Lichtenegger, Felix S. ;
Schneider, Stephanie ;
Metzeler, Klaus H. ;
Fiegl, Michael ;
Spiekermann, Karsten ;
Baeuerle, Patrick A. ;
Hiddemann, Wolfgang ;
Riethmueller, Gert ;
Subklewe, Marion .
BLOOD, 2014, 123 (03) :356-365
[19]   Peripheral blood T cells in acute myeloid leukemia (AML) patients at diagnosis have abnormal phenotype and genotype and form defective immune synapses with AML blasts [J].
Le Dieu, Rifca ;
Taussig, David C. ;
Ramsay, Alan G. ;
Mitter, Richard ;
Miraki-Moud, Faridah ;
Fatah, Rewas ;
Lee, Abigail M. ;
Lister, T. Andrew ;
Gribben, John G. .
BLOOD, 2009, 114 (18) :3909-3916
[20]   Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses [J].
Morris, Anna B. ;
Adams, Layne E. ;
Ford, Mandy L. .
FRONTIERS IN IMMUNOLOGY, 2018, 9