Immunosuppression and outcomes in adult patients with de novo acute myeloid leukemia with normal karyotypes
| العنوان: | Immunosuppression and outcomes in adult patients with de novo acute myeloid leukemia with normal karyotypes |
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| المؤلفون: | Francesca Ferraro, Jacqueline E. Payton, Keegan A. Christensen, Lukas D. Wartman, Ann-Kathrin Eisfeld, Sai Mukund Ramakrishnan, Ryan B. Day, Matthew J. Christopher, Geoffrey L. Uy, Michael P. Rettig, Peter Westervelt, Matthew J. Schuelke, Catrina Fronick, Robert S. Fulton, Jack Baty, Clara D. Bloomfield, David H. Spencer, Timothy J. Ley, Christopher A. Miller, Margaret O’Laughlin, Sharon Heath, Jessica Kohlschmidt, Nichole M. Helton, John F. DiPersio, Matthew J. Walter, John S. Welch, Daniel C. Link |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | National Academy of Sciences, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Adult, CD4-Positive T-Lymphocytes, Male, LAG3, Medical Sciences, medicine.medical_treatment, T cell, Karyotype, acute myeloid leukemia, chemotherapy, Immune system, Recurrence, Risk Factors, hemic and lymphatic diseases, medicine, Immune Tolerance, Humans, Chemotherapy, cancer genomics, Multidisciplinary, immunosuppression, business.industry, Sequence Analysis, RNA, T-cell receptor, Remission Induction, Myeloid leukemia, Immunosuppression, Biological Sciences, Middle Aged, Th1 Cells, Prognosis, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Treatment Outcome, Cancer research, Female, Bone marrow, checkpoints, business, Transcriptome |
| الوصف: | Significance Current acute myeloid leukemia (AML) risk assessment relies on cytogenetics and gene-sequencing studies but is imperfect, especially for patients with normal karyotypes and intermediate risk. To understand factors associated with excellent responses in these patients, we compared genetic and transcriptional data from patients with first remissions lasting more than 5 y after chemotherapy, to matched controls with first remissions lasting fewer than 2 y. AML cells from patients with early relapse displayed an immunosuppressive phenotype that blocked CD4 T cell activation via the T cell receptor; the long first-remission AML cells did not display this phenotype. Inhibiting LAG3 reversed this immunosuppression in most tested cases. This immunosuppressive phenotype may help to stratify risk of relapse at presentation, and outcomes. Acute myeloid leukemia (AML) patients rarely have long first remissions (LFRs; >5 y) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, standard remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing, and functional immunologic studies, we characterized 28 normal karyotype (NK)-AML patients with >5 y first remissions after chemotherapy (LFRs) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 y (standard first remissions [SFRs]). Our combined analyses indicated that genetic-risk profiling at presentation (as defined by European LeukemiaNet [ELN] 2017 criteria) was not sufficient to explain the outcomes of many SFR cases. Single-cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD4+ Th1 cells; these T cells expressed an exhaustion signature and were resistant to activation by T cell receptor stimulation in the presence of autologous AML cells. T cell activation could be restored by removing the AML cells or blocking the inhibitory major histocompatibility complex class II receptor, LAG3. Most LFR cases did not display these features, suggesting that their AML cells were not as immunosuppressive. These findings were confirmed and extended in an independent set of 50 AML cases representing all ELN 2017 risk groups. AML cell–mediated suppression of CD4+ T cell activation at presentation is strongly associated with unfavorable outcomes in AML patients treated with standard chemotherapy. |
| اللغة: | English |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f5bf441e61c9a78aa54a4fcd8ecf9f8a http://europepmc.org/articles/PMC8673586 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....f5bf441e61c9a78aa54a4fcd8ecf9f8a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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