# PD-1 Expression Promotes Immune Evasion in B-ALL

## TL;DR

This study shows that PD-1 expression helps B-cell acute lymphoblastic leukemia (B-ALL) cells evade the immune system, and targeting PD-1 could offer new treatment options for childhood B-ALL.

## Contribution

The study identifies PD-1 as a novel marker and therapeutic target for immune evasion in B-ALL.

## Key findings

- PD-1 expression is upregulated in preleukemic cells and correlates with leukemia conversion in mice and humans.
- PD-1 expression reduces antitumor immune responses but makes leukemic cells responsive to immune checkpoint blockade.
- Targeting PD-1 restores NK cell-mediated tumor cell killing and eliminates tumor cells in mouse models.

## Abstract

Background/Objectives: 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 through unknown mechanisms. Methods and Results: Here, we identify the upregulation of PD-1 expression in preleukemic cells, triggered by Pax5 inactivation in mice and correlating with the time of conversion to leukemia, as a novel marker that favors leukemia evasion. This increase in PD-1 expression is apparent across diverse molecular B-ALL subtypes, both in mice and humans. PD-1 is not required for B-cell leukemogenesis, but, in the absence of PD-1, tumor cells express NK cell inhibitory receptors, highlighting the necessity for leukemic cells to evade the host’s NK immune response in order to exit the bone marrow. PD-1 expression reduces natural antitumor immune responses, but it sensitizes leukemic cells to immune checkpoint blockade strategies in mice and humans. PD-1 targeting confers clinical benefits by restoring NK-mediated tumor cell killing in vitro and eliminating tumor cells in vivo in mice engrafted with B-ALL. Conclusions: These results identify PD-1 as a new therapeutic target against leukemic progression, providing new opportunities for the treatment and possibly also the prevention of childhood B-ALL.