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

Milad Abolhalaj, Viktor Sincic, Henrik Lilljebjörn, Carl Sandén, Alar Aab, Karin Hägerbrand, Peter Ellmark, Carl Borrebaeck, Thoas Fioretos, Kristina Lundberg

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

Sammanfattning



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.
Originalspråksvenska
Sidor (från-till)3023-3032
TidskriftCancer Medicine
Volym11
Nummer15
Tidigt onlinedatum2022 mars 16
DOI
StatusPublished - 2022

Ämnesklassifikation (UKÄ)

  • Immunologi inom det medicinska området
  • Cancer och onkologi

Fria nyckelord

  • T-cell
  • RNA-Sequencing
  • acute myeloid leukemia (AML)
  • TP53
  • Immunotherapy

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