Pax5 Inactivation Unleashes PD-1 expression and Promotes Immune Evasion in B-ALL

In children developing B-cell acute lymphoblastic leukemia (B-ALL), an immune evasion event takes place where otherwise "silent" preleukemic cells undergo a malignant transformation while escaping immune control, often by unknown mechanisms. Here, we identify PAX5 inactivation as a mechanism that favors leukemia immune evasion by triggering a PD-1-mediated immune checkpoint response. Mechanistically, PAX5 loss promotes the ability of preleukemic cells to induce PD-1 expression, correlating with the time of conversion to leukemia. This increase in PD1 expression is apparent across diverse molecular B-ALL subtypes, both in mice and humans. The PAX5-dependent PD-1 expression reduces natural anti-tumor immune responses, but it sensitizes leukemic cells to immune checkpoint blockade strategies in mice and humans. PD-1 targeting confers clinical benefit by restoring NK-mediated tumor cell killing in vitro and eliminating tumor cells in vivo in mice engrafted with B-ALL. These results reveal a previously unrecognized role for PAX5 inactivation in protecting B-ALL blasts from NK-mediated immune surveillance in vivo, identifying PAX5 as a regulator of anti-tumor immunity and providing new opportunities for the treatment or prevention of childhood B-ALL.