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Transcriptional profiling demonstrates altered characteristics of CD8 + cytotoxic T-cells and regulatory T-cells in TP53-mutated acute myeloid leukemia
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- Abolhalaj, Milad (author)
- Lund University,Lunds universitet,Create Health,Annan verksamhet, LTH,Lunds Tekniska Högskola,Institutionen för immunteknologi,Institutioner vid LTH,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Other operations, LTH,Faculty of Engineering, LTH,Department of Immunotechnology,Departments at LTH,Faculty of Engineering, LTH,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Sincic, Viktor (author)
- Lund University,Lunds universitet,Create Health,Annan verksamhet, LTH,Lunds Tekniska Högskola,Institutionen för immunteknologi,Institutioner vid LTH,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Other operations, LTH,Faculty of Engineering, LTH,Department of Immunotechnology,Departments at LTH,Faculty of Engineering, LTH,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Lilljebjörn, Henrik (author)
- Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Translationella genomiska och funktionella studier av leukemi,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,Translational Genomic and Functional Studies of Leukemia,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- (creator_code:org_t)
- 2022-03-16
- 2022
- Swedish.
- In: Cancer Medicine. - : Wiley. - 2045-7634. ; 11:15, s. 3023-3032
- Journal article (peer-reviewed)
Abstract
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- Background: Acute myeloid leukemia (AML) patients have limited effect from T-cell-based therapies, such as PD-1 and CTLA-4 blockade. However, recent data indicate that AML patients with TP53 mutation have higher immune infiltration and other immunomodulatory therapies could thus potentially be effective. Here, we performed the transcriptional analysis of distinct T-cell subpopulations from TP53-mutated AML to identify gene expression signatures suggestive of altered functional properties.Methods: CD8+ cytotoxic T lymphocytes (CTLs), conventional helper T cells (Th), and regulatory T cells (Tregs) were sorted from peripheral blood of AML patients with TP53 mutation (n = 5) and healthy donors (n = 3), using FACS, and the different subpopulations were subsequently subjected to RNA-sequencing. Differentially expressed genes were identified and gene set enrichment analysis (GSEA) was performed to outline altered pathways and exhaustion status. Also, expression levels for a set of genes encoding established and emerging immuno-oncological targets were defined.Results: The results showed altered transcriptional profiles for each of the T-cell subpopulations from TP53-mutated AML as compared to control subjects. IFN-α and IFN-γ signaling were stronger in TP53-mutated AML for both CTLs and Tregs. Furthermore, in TP53-mutated AML as compared to healthy controls, Tregs showed gene expression signatures suggestive of metabolic adaptation to their environment, whereas CTLs exhibited features of exhaustion/dysfunction with a stronger expression of TIM3 as well as enrichment of a gene set related to exhaustion.Conclusions: The results provide insights on mechanisms underlying the inadequate immune response to leukemic cells in TP53-mutated AML and open up for further exploration toward novel treatment regimens for these patients.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- T-cell
- RNA-Sequencing
- acute myeloid leukemia (AML)
- TP53
- Immunotherapy
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- Ellmark, Peter
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