Transcriptional profiling demonstrates altered characteristics of CD8+ cytotoxic T‐cells and regulatory T‐cells in TP53‐mutated acute myeloid leukemia
Abstract 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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-08-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.4661 |
| _version_ | 1811341836507152384 |
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| author | Milad Abolhalaj Viktor Sincic Henrik Lilljebjörn Carl Sandén Alar Aab Karin Hägerbrand Peter Ellmark Carl A. K. Borrebaeck Thoas Fioretos Kristina Lundberg |
| author_facet | Milad Abolhalaj Viktor Sincic Henrik Lilljebjörn Carl Sandén Alar Aab Karin Hägerbrand Peter Ellmark Carl A. K. Borrebaeck Thoas Fioretos Kristina Lundberg |
| author_sort | Milad Abolhalaj |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-13T19:00:00Z |
| format | Article |
| id | doaj.art-20b503bd7a874918ae750066e8a54cb8 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-04-13T19:00:00Z |
| publishDate | 2022-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-20b503bd7a874918ae750066e8a54cb82022-12-22T02:34:06ZengWileyCancer Medicine2045-76342022-08-0111153023303210.1002/cam4.4661Transcriptional profiling demonstrates altered characteristics of CD8+ cytotoxic T‐cells and regulatory T‐cells in TP53‐mutated acute myeloid leukemiaMilad Abolhalaj0Viktor Sincic1Henrik Lilljebjörn2Carl Sandén3Alar Aab4Karin Hägerbrand5Peter Ellmark6Carl A. K. Borrebaeck7Thoas Fioretos8Kristina Lundberg9Department of Immunotechnology, Medicon Village (Building 406) Lund University Lund SwedenDepartment of Immunotechnology, Medicon Village (Building 406) Lund University Lund SwedenDivision of Clinical Genetics, Department of Laboratory Medicine Lund University Lund SwedenDivision of Clinical Genetics, Department of Laboratory Medicine Lund University Lund SwedenDepartment of Immunotechnology, Medicon Village (Building 406) Lund University Lund SwedenAlligator Bioscience AB Medicon Village Lund SwedenDepartment of Immunotechnology, Medicon Village (Building 406) Lund University Lund SwedenDepartment of Immunotechnology, Medicon Village (Building 406) Lund University Lund SwedenDivision of Clinical Genetics, Department of Laboratory Medicine Lund University Lund SwedenDepartment of Immunotechnology, Medicon Village (Building 406) Lund University Lund SwedenAbstract 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.https://doi.org/10.1002/cam4.4661acute myeloid leukemiaimmunotherapyRNA‐sequencingT‐cellsTP53 |
| spellingShingle | Milad Abolhalaj Viktor Sincic Henrik Lilljebjörn Carl Sandén Alar Aab Karin Hägerbrand Peter Ellmark Carl A. K. Borrebaeck Thoas Fioretos Kristina Lundberg Transcriptional profiling demonstrates altered characteristics of CD8+ cytotoxic T‐cells and regulatory T‐cells in TP53‐mutated acute myeloid leukemia Cancer Medicine acute myeloid leukemia immunotherapy RNA‐sequencing T‐cells TP53 |
| title | Transcriptional profiling demonstrates altered characteristics of CD8+ cytotoxic T‐cells and regulatory T‐cells in TP53‐mutated acute myeloid leukemia |
| title_full | Transcriptional profiling demonstrates altered characteristics of CD8+ cytotoxic T‐cells and regulatory T‐cells in TP53‐mutated acute myeloid leukemia |
| title_fullStr | Transcriptional profiling demonstrates altered characteristics of CD8+ cytotoxic T‐cells and regulatory T‐cells in TP53‐mutated acute myeloid leukemia |
| title_full_unstemmed | Transcriptional profiling demonstrates altered characteristics of CD8+ cytotoxic T‐cells and regulatory T‐cells in TP53‐mutated acute myeloid leukemia |
| title_short | Transcriptional profiling demonstrates altered characteristics of CD8+ cytotoxic T‐cells and regulatory T‐cells in TP53‐mutated acute myeloid leukemia |
| title_sort | transcriptional profiling demonstrates altered characteristics of cd8 cytotoxic t cells and regulatory t cells in tp53 mutated acute myeloid leukemia |
| topic | acute myeloid leukemia immunotherapy RNA‐sequencing T‐cells TP53 |
| url | https://doi.org/10.1002/cam4.4661 |
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