Intrinsic and extrinsic causes of malignancies in patients with primary immunodeficiency disorders.

Malignancies occur with a higher incidence rate and manifest earlier in life in patients with primary immunodeficiency disorders (PIDs) than in the general population. However, no universal mechanism of malignancy predisposition in patients with PIDs has been determined. Despite strong support for the physiologic role of tumor immunosurveillance and the increasing success of strategies in immunologic tumor therapy, which include checkpoint inhibition, mAbs, and engineered T-cell antigen receptors, the incidence and pattern of malignancies in patients with PIDs do not reflect an increased tumor immune escape per se. In contrast, malignancies appear to be restricted to either (1) tissue types bearing the same molecular defect that underlies the PID, such as syndromes of DNA repair deficiency or immune cell-specific maturation or functional defects that suggest a cell-intrinsic oncogenic basis, or (2) other tissues when they are infected by transforming viruses or chronically inflamed, pointing toward extrinsic causes for transformation that are potentially facilitated by but not predominantly caused by a lack of immunosurveillance. Based on recent studies of pre-existing conditions in patients with malignancies and on malignancies in large PID cohorts, we conclude that a large part of tumor predisposition in patients with PIDs is derived from the same molecular defect as the immunodeficiency itself. The presented concept elucidates diverse pathomechanisms and risks of malignancies in patients with PIDs in light of current tumor immune therapies.