Running titlePurine nucleotide metabolism regulates MICA expression Keywords Immunology, Warburg effect, Purine, Natural killer cells (NK cells), Metabolism, NKG2D ligands, Purine metabolism, Glucose metabolism, Immunometabolism, Immunosurveillance Abstract Expression of the cell surface glycoprotein MHC class I polypeptide-related sequence A (MICA) is induced in dangerous, abnormal or 'stressed' cells, including cancer cells, virus-infected cells and rapidly proliferating cells. MICA is recognized by the activating immune cell receptor NKG2D, providing a mechanism by which immune cells can identify and potentially eliminate pathological cells. Immune recognition through NKG2D is implicated in cancer, atherosclerosis, transplant rejection and inflammatory diseases such as rheumatoid arthritis. Despite the wide range of potential therapeutic applications of MICA manipulation, the factors that control MICA expression are unclear. Here we use metabolic interventions and metabolomic analyses to show that the transition from quiescent cellular metabolism to a 'Warburg' or biosynthetic metabolic state induces MICA expression. Specifically, we show that glucose transport into the cell and active glycolytic metabolism are necessary to upregulate MICA expression. Active purine synthesis is necessary to support this effect of glucose, and increases in purine nucleotide levels are sufficient to induce MICA expression.Metabolic induction of MICA expression directly influences NKG2D-dependent cytotoxicity by immune cells. These findings support a model of MICA regulation whereby the purine metabolic activity of individual cells is reflected by cell surface MICA expression and is the subject of surveillance by NKG2D receptor-expressing immune cells.

Prostate-specific antigen (PSA) is widely used as a biomarker in the detection of prostate cancer and for decision making regarding treatment options, response to therapy, and clinical follow-up. Despite its widespread use, it is well recognised that PSA has suboptimal performance as a screening tool due to poor specificity, resulting in high negative biopsy rates and potential ‘over-diagnosis’ and ‘over-treatment’ of clinically insignificant cancers. In particular, PSA does not reliably distinguish either cancer from benign prostatic conditions, or ‘clinically significant’ from ‘indolent cancers’, and it is inaccurate in predicting disease burden and response to treatment. There is an urgent demand for novel biomarkers to address these clinical needs. This article provides an update on the novel candidate biomarkers in development, which have shown potential for improving the detection of clinically significant cases of this malignancy.

The safety and efficacy of combining the IDH1 inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO+VEN) +/- azacitidine (AZA; IVO+VEN+AZA) was evaluated in four cohorts of patients with IDH1-mutated myeloid malignancies (n=31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO+VEN+AZA vs. IVO+VEN was 90% vs. 83%. Among MRD-evaluable patients (N=16) 63% attained MRD-negative remissions; IDH1 mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (N=14). Median EFS and OS were 36 (95% CI: 23-NR) and 42 (95% CI: 42-NR) months. Patients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked co-occurring mutations, anti-apoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1 mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.