The Δ133p53β isoform promotes an immunosuppressive environment leading to aggressive prostate cancer

Abstract

Prostate cancer is the second most common cancer in men, for which there are no reliable biomarkers or targeted therapies. Here we demonstrate that elevated levels of Δ133TP53β isoform characterize prostate cancers with immune cell infiltration, particularly T cells and CD163+ macrophages. These cancers are associated with shorter progression-free survival, Gleason scores ≥ 7, and an immunosuppressive environment defined by a higher proportion of PD-1, PD-L1 and colony-stimulating factor 1 receptor (CSF1R) positive cells. Consistent with this, RNA-seq of tumours showed enrichment for pathways associated with immune signalling and cell migration. We further show a role for hypoxia and wild-type p53 in upregulating Δ133TP53 levels. Finally, AUC analysis showed that Δ133TP53β expression level alone predicted aggressive disease with 88% accuracy. Our data identify Δ133TP53β as a highly accurate prognostic factor for aggressive prostate cancer.

Intronic TP53 Polymorphisms Are Associated with Increased Δ133TP53 Transcript, Immune Infiltration and Cancer Risk

“…The presence of immune cells that promote an immunosuppressive environment within PCa has been associated with advanced PCa [47,48]. Consistent with this, we demonstrated CD3+ T cells can predict poor PCa outcomes with 79% accuracy and CD163+ Mφ cells with 68% accuracy [38]. Thus, we assessed the influence of the three TP53 SNP combinations on immune cell content.…”

“…Several studies have now shown that aberrant expression of some p53 isoforms contribute to diseases, including cancer [5,6,35]. Elevated transcript levels of the ∆133TP53 isoforms are associated with poor patient outcomes in breast [36,37], prostate [38] and colorectal cancers [39] and the ∆133TP53β isoform level is associated with increased immune cell infiltration in glioblastoma [35] and prostate cancer [38]. Other evidence suggests that ∆133p53 isoforms can antagonise canonical full-length p53 tumour suppressor activity and have multiple intrinsic tumour-promoting capacities [40].…”

Accessing a New Dimension in TP53 Biology: Multiplex Long Amplicon Digital PCR to Specifically Detect and Quantitate Individual TP53 Transcripts

“…To date, the p53 field has predominantly used correlation analysis to try to draw inferential conclusions about which TP53 transcript 5' ends are associated with which 3' ends [11][12][13][14][15]. Our assays now provide the ability for researchers to detect and quantitate full length TP53 transcripts, without the need to draw inferential conclusions, and so can facilitate the understanding of TP53 isoform biology at a more comprehensive level.…”

“…They share five central exons in common, which span 618 bp, therefore to determine which 5' end and 3' end are part of the same transcript requires amplification of >618 bp. Most PCR-based assays of TP53 transcript abundance, including our own work, have focused on quantifying the individual transcript ends [8][9][10][11][12][13]. These studies have shown that the levels of certain 5' or 3' ends are significantly associated with patient prognosis in a number of cancer types, presumably reflecting the biological functions of the p53 protein sequences encoded by these alternatively-spliced RNA ends.…”

“…These studies have shown that the levels of certain 5' or 3' ends are significantly associated with patient prognosis in a number of cancer types, presumably reflecting the biological functions of the p53 protein sequences encoded by these alternatively-spliced RNA ends. For example, glioblastoma, colorectal or prostate cancer patients with the highest levels of the ∆133TP53 5' end or the TP53α 3' end have relatively poor prognosis [11][12][13]. In contrast, low levels of TP53β and TP53γ 3' ends have been associated with poor prognosis in breast cancer [9,10].…”