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

• Published in: Cancer medicine (Malden, MA) Vol. 11; no. 15; pp. 3023 - 3032
• Main Authors: Abolhalaj, Milad, Sincic, Viktor, Lilljebjörn, Henrik, Sandén, Carl, Aab, Alar, Hägerbrand, Karin, Ellmark, Peter, Borrebaeck, Carl A. K., Fioretos, Thoas, Lundberg, Kristina
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.08.2022; John Wiley and Sons Inc; Wiley
• Subjects: Acute myeloid leukemia; acute myeloid leukemia (AML); Basic Medicine; Bone marrow; Cancer and Oncology; Cancer och onkologi; CD8 antigen; Clinical Medicine; Cytotoxicity; Flow cytometry; Gene expression; Gene set enrichment analysis; Genomes; Immunologi inom det medicinska området; Immunologi inom det medicinska området (Här ingår: Cell- och immunterapi); Immunology in the medical area; Immunology in the Medical Area (including Cell and Immunotherapy); Immunomodulation; Immunoregulation; Immunotherapy; Interferon; Klinisk medicin; Leukemia; Lymphocytes T; Medical and Health Sciences; Medical prognosis; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mutation; p53 Protein; Patients; Peripheral blood; Principal components analysis; RNA-Sequencing; T-cell; TP53; Transcription; T‐cells; Variance analysis; RNA-sequencing; T-cells; acute myeloid leukemia; TP53; immunotherapy
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.4661

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. Cytotoxic and regulatory T‐cells are transcriptionally altered in AML patients with TP53 mutation. The transcriptional profiles suggest metabolic adaptation and proliferation of Tregs, and exhaustion/dysfunction of cytotoxic T‐cells. Hence, these mechanisms could contribute to the inadequate immune response to leukemic cells and thus pave the way for novel treatment regimens for these patients.