# PDCD1 as a targetable immune checkpoint hub: therapeutic insights for ibrutinib-resistant CLL management

## TL;DR

This study identifies PDCD1 as a key immune checkpoint involved in resistance to ibrutinib in chronic lymphocytic leukemia, suggesting new treatment strategies.

## Contribution

The study reveals PDCD1 as a novel therapeutic target for ibrutinib-resistant CLL through immune checkpoint pathways.

## Key findings

- PDCD1, CD1C, and ITGB2 were identified as common hub genes in ibrutinib-resistant CLL.
- PDCD1 is regulated by ceRNA networks and transcription factors, contributing to drug resistance.
- Blocking PDCD1 (PD-1) is proposed as a strategy to overcome ibrutinib resistance in CLL.

## Abstract

Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow, specifically involving the overproduction of abnormal lymphocytes. Using two independent datasets (GSE249956 and GSE98206), differentially expressed genes (DEGs) were identified between ibrutinib-resistant and sensitive CLL samples. Protein–protein interaction (PPI) network analysis revealed key hub genes related to resistance. Three common hub genes were shared across datasets: PDCD1, CD1C, and ITGB2. PDCD1, encoding the immune checkpoint protein PD-1, was selected for deeper investigation due to its important role in immune regulation and relevance in drug resistance. Post-transcriptional regulation of PDCD1 was explored by the construction of competing endogenous RNA (ceRNA) networks linking lncRNAs and miRNAs that may modulate PDCD1 expression, indicating complex upstream regulatory mechanisms. Transcription factors potentially regulating PDCD1 were identified, suggesting layers of transcriptional control contributing to ibrutinib resistance. Drug-gene interaction analysis showed that although PDCD1 is not directly targeted by ibrutinib. This implicates immune checkpoint blockade as a promising therapeutic strategy to overcome or complement resistance in CLL. In the broader context, PD-1 expression in CLL cells is linked to active proliferation and immune escape. Overall, our findings emphasize PDCD1’s central role in ibrutinib resistance through immune checkpoint pathways and support the rationale for combining BTK inhibitors with immune checkpoint blockade therapies in resistant CLL cases.

The online version contains supplementary material available at 10.1007/s10238-025-01942-2.