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

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-alpha and IFN-gamma 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.

Automated summary

The study revealed altered transcriptional profiles in different T-cell subpopulations from TP53-mutated AML patients compared to healthy controls. Both CTLs and Tregs in TP53-mutated AML showed stronger IFN-alpha and IFN-gamma signaling. Tregs in TP53-mutated AML displayed gene expression patterns suggesting metabolic adaptation, while CTLs exhibited features of exhaustion/dysfunction with increased expression of TIM3 and enrichment of exhaustion-related gene set.