PD-1 expression identifies proliferating malignant CLL B cells and is a potential biomarker of response to BTK inhibitor therapy

• 成果类型: Article
• 署名作者: Chang, Andres; Pelletier, Adam N.; McGuire, Donald J.; Tsagiopoulou, Maria; Karipidou, Maria; Ayers, Amy; Leal, Alyssa M. K.; Churnetski, Michael C.; O'Leary, Colin B.; Switchenko, Jeffrey M.; Davis, Carl; Frank, David A.; Koff, Jean L.; Cohen, Jonathon B.; Sekaly, Rafick P.; Stamatopoulos, Kostas; Flowers, Christopher R.; Ahmed, Rafi
• 署名单位: University of Texas System; UTMD Anderson Cancer Center; Emory University; Emory University; Emory University; Rollins School Public Health
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11213
• DOI: 10.1073/pnas.2426935122
• 发表日期: 2025-09-09
• 关键词: chronic lymphocytic-leukemia; t-cells; activation; receptor; microenvironment; exhaustion; features; outcomes

摘要

Chronic lymphocytic leukemia (CLL) remains incurable despite treatment advances, and a major challenge is that biomarkers that predict response and resistance to current therapies are lacking. We report that activated and proliferating malignant CLL B cells in circulation express PD-1, a protein normally expressed in T cells. PD-1 expression is absent in circulating B cells from healthy controls and nonmalignant B cells from patients with CLL. Circulating PD-1+ CLL cells are found in all treatment na & iuml;ve patients, regardless of immunoglobulin heavy-chain variable region gene mutation status or cytogenetic abnormalities. PD-1+ CLL cells are transcriptionally distinct compared to PD-1-CLL cells and upregulate genes associated with cell activation, proliferation, and B cell receptor (BCR) and toll-like receptor (TLR) signaling. Indeed, ex vivo stimulation of the BCR and TLR9 readily increased PD-1 expression in CLL cells from treatment-na & iuml;ve patients within 24 h, an effect that was blocked by Bruton's tyrosine kinase inhibitors (BTKi). More importantly, patients initiating BTKi therapy experienced profound reductions in circulating PD-1+ CLL cell numbers within 1 mo, which is in line with reduction in Ki-67+CLL cells. Elevated percentages of circulating PD-1+ CLL cells also preceded a clinical diagnosis of disease progression in patients receiving BTKi. Thus, our findings indicate that PD-1 expression is a potential biomarker to identify proliferating CLL cells in vivo and will be useful to predict response and resistance to BTKi. In addition, eliminating PD-1+ CLL cells with depleting anti-PD-1 monospecific or bispecific antibodies should be explored as a potential therapeutic strategy.