TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype

Abstract

Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. Here we characterize the immunological features of the malignant clone and alterations in the immune microenvironment in TP53 mutant and wild type MDS and sAML patients. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of TP53 mutant patients, which is associated with MYC upregulation and marked down-regulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, TP53 mutant patients display significantly reduced numbers of bone marrow infiltrating OX40+ cytotoxic T-cells and helper T-cells, as well as decreased ICOS+ and 4-1BB+ NK cells. Further, highly immunosuppressive regulatory T-cells (i.e., ICOSHigh/PD-1neg) and MDSCs (PD-1low) are expanded in TP53 mutant cases. Finally, a higher proportion of bone marrow infiltrating ICOSHigh/PD-1neg Tregs is a highly significant independent predictor of overall survival. We conclude the microenvironment of TP53 mutant MDS and sAML has an immune privileged, evasive phenotype that may be a primary driver of poor outcomes, and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly-defined subpopulation.

Altered Spatial Composition of the Immune Cell Repertoire in Association to CD34+ Blasts in Myelodysplastic Syndromes and Secondary Acute Myeloid Leukemia

“…In addition, another study presented data demonstrating that patients with TP53 mutations exhibited a reduced number of helper T cells, but a significant increase in Treg and MDSC. These results suggest that the tumor microenvironment (TME) of TP53 mutated MDS and sAML might display an immune escape phenotype [ 56 ].…”

From Clonal Hematopoiesis to Therapy-Related Myeloid Neoplasms: The Silent Way of Cancer Progression

“…Moreover, TP53 clones expand over time and drive transformation to t-MN, being the bulk of the malignant clone at diagnosis [61]. This intrinsic advantage may be related to a specific TP53-related immune escape phenotype, as shown by a recent study where TP53 mutant cases showed an imbalance of checkpoint molecules and expansion of highly immunosuppressive regulatory T cells and myeloid-derived suppressor cells [62] (Figure 2). PPM1D is the second most frequently mutated gene, accounting for 20% of t-MN cases and, as mentioned, it has been linked to previous cancer treatment exposure [63].…”

MicroRNA-34a: Potent Tumor Suppressor, Cancer Stem Cell Inhibitor, and Potential Anticancer Therapeutic

“…The role of the CSC niche in modulating the level of tumor immunity is of great interest. TP53 mutations in myelodysplastic syndromes and secondary AML patients confer an immunosuppressive phenotype (Sallman et al, 2020). Those TP53 mutant patients display significantly reduced numbers of cytotoxic T lymphocytes (CTLs) and helper T cells, as well as decreased NK cells with increased regulatory T cells (Treg cells) and myeloid-derived suppressor cells (MDSCs) (Sallman et al, 2020).…”

“…TP53 mutations in myelodysplastic syndromes and secondary AML patients confer an immunosuppressive phenotype (Sallman et al, 2020). Those TP53 mutant patients display significantly reduced numbers of cytotoxic T lymphocytes (CTLs) and helper T cells, as well as decreased NK cells with increased regulatory T cells (Treg cells) and myeloid-derived suppressor cells (MDSCs) (Sallman et al, 2020). Notably, downregulation of miR-34a was observed in TP53 mutant patients (Sallman et al, 2020), suggesting a close link between miR-34a expression levels, p53 mutation status, and tumor immunity.…”