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Transcriptional profiling demonstrates altered characteristics of CD8 + cytotoxic T-cells and regulatory T-cells in TP53-mutated acute myeloid leukemia

Abolhalaj, Milad LU ; Sincic, Viktor LU ; Lilljebjörn, Henrik LU orcid ; Sandén, Carl LU ; Aab, Alar LU ; Hägerbrand, Karin LU ; Ellmark, Peter LU ; Borrebaeck, Carl LU ; Fioretos, Thoas LU and Lundberg, Kristina LU (2022) In Cancer Medicine 11(15). p.3023-3032
Abstract (Swedish)


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... (More)


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.
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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
T-cell, RNA-Sequencing, acute myeloid leukemia (AML), TP53, Immunotherapy
in
Cancer Medicine
volume
11
issue
15
pages
3023 - 3032
publisher
Wiley-Blackwell
external identifiers
  • pmid:35297213
  • scopus:85126305565
ISSN
2045-7634
DOI
10.1002/cam4.4661
language
Swedish
LU publication?
yes
id
f6e78fbd-d5e5-4afd-b4cc-db90f8a78aa8
date added to LUP
2022-04-13 09:20:06
date last changed
2023-02-19 18:06:20
@article{f6e78fbd-d5e5-4afd-b4cc-db90f8a78aa8,
  abstract     = {{<br/><br/>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.<br/><br/>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.<br/><br/>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.<br/><br/>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.<br/>}},
  author       = {{Abolhalaj, Milad and Sincic, Viktor and Lilljebjörn, Henrik and Sandén, Carl and Aab, Alar and Hägerbrand, Karin and Ellmark, Peter and Borrebaeck, Carl and Fioretos, Thoas and Lundberg, Kristina}},
  issn         = {{2045-7634}},
  keywords     = {{T-cell; RNA-Sequencing; acute myeloid leukemia (AML); TP53; Immunotherapy}},
  language     = {{swe}},
  month        = {{03}},
  number       = {{15}},
  pages        = {{3023--3032}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Cancer Medicine}},
  title        = {{Transcriptional profiling demonstrates altered characteristics of CD8 + cytotoxic T-cells and regulatory T-cells in TP53-mutated acute myeloid leukemia}},
  url          = {{http://dx.doi.org/10.1002/cam4.4661}},
  doi          = {{10.1002/cam4.4661}},
  volume       = {{11}},
  year         = {{2022}},
}