LAUSR

I the current issue of Transplantation, Utrero-Rico et al report an association between risk of posttransplant malignancy and peak monocytic myeloid-derived suppressor cell (M-MDSC) responses early after renal transplantation. This is an important clinical observation that demands a mechanistic explanation. MDSC are a heterogeneous group of immune-regulatory myeloid cells known to accumulate in peripheral blood under chronic inflammatory conditions. These cells nonspecifically suppress T-cells and represent part of a systemic counterresponse to prolonged inflammation. MDSC were originally described in patients with advanced cancers. In various tumor entities, high numbers of circulating MDSC are associated with later tumor stages, worse prognoses, and weaker therapeutic responses. Therefore, Utrero-Rico et al propose a direct causal relationship between elevated numbers of MDSC after transplantation and promotion of tumors. More specifically, they hypothesize that MDSC responses induced by surgical inflammatory or T-cell alloimmunity enable the early development of tumors, perhaps by suppressing T-cells–mediated immunity against malignant cells or supporting their growth through secretion of trophic factors. Although this mechanism seems plausible, there are several possible alternative pathophysiological explanations (Figure 1). Human MDSC are conventionally divided into 3 main subtypes according to phenotype and function: monocytic MDSC, polymorphonuclear MDSC, and early-stage MDSC. The article of Utrero-Rico et al describes the kinetics of M-MDSC in the early posttransplant period. In virtually all patients, the authors observed an increase in M-MDSC counts at 7-day posttransplant, which peaked at 14 days and then declined over 1 year but remained elevated compared to pretransplant levels. This pattern of M-MDSC accumulation is broadly consistent with previous studies in kidney and intestinal transplant recipients. Of course, it is striking that this early enrichment and gradual restitution of M-MDSC numbers matches so closely to the schedule of immunosuppressive therapy after renal transplantation, particularly glucocorticoid dosing. This suggests an alternative explanation for the reported association—namely, that posttransplant malignancy risk and M-MDSC numbers may covary in response to steroid exposure, but they might not be causally related effects. Human MDSC subsets are identified in blood by flow cytometry as CD33 CD11b lineage leucocytes; however, their crucial defining characteristic is low HLA-DR expression. Although this is a universally accepted phenotypic definition of MDSC, it has limitations in transplant recipients who receive high-dose prednisone because glucocorticoids downregulate HLA-DR expression in monocytes, making them phenotypically indistinguishable from M-MDSC (Figure 2A). To demonstrate this effect also occurs in vivo, circulating M-MDSC numbers were measured in a healthy volunteer treated with prednisone (Figure 2B). Steroid exposure led to a gradual downregulation of HLA-DR expression over 5 days, which increased the measured frequency (2.2-fold) and absolute number (4.6-fold) of M-MDSC. Hence, prednisone alone could account for the increase in circulating M-MDSC reported by Utrero-Rico et al in most patients after transplantation. Importantly, the key observation of Utrero-Rico et al was that patients who developed posttransplant malignancy were those with peak M-MDSC counts well outside the distribution in patients without malignancies. This difference might reflect a preexisting alteration in the myeloid compartment or an exaggerated response to immunosuppression. It is well known that glucocorticoid responsiveness of human monocytes is highly variable between individuals owing partly to genetic polymorphisms. Tellingly, a recent study in patients with focal segmental glomerulosclerosis discriminated between patients who responded well to prednisone treatment and exhibited high induction of M-MDSC, versus patients who responded poorly and only weakly upregulated M-MDSC. It is presently unknown whether monocytes that downregulate HLA-DR in response to glucocorticoids are actually the same as M-MDSC in terms of their program of cellular differentiation and immunological function. This Commentary