Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
CLL cells express PD-1 when actively growing, and increased PD-1 expression may be an early sign of resistance to BTK inhibitor therapy.
Who Performed the Research and Where Was it Presented:
Dr. Andres Chang from Emory University and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting 2024.
Background:
PD-1 is an immune checkpoint, a protein that controls and regulates the function of specific immune cells, including T cells. Under normal conditions, PD-1 acts as a brake on T cells by making sure that the T cells don’t overreact during an immune response and cause damage to healthy tissues. PD-1 inhibitors are drugs that remove the brake on T cells and allow them to kill cancer cells. While PD-1 inhibitors have been effective in treating various solid tumors, they have been less successful in treating blood cancers, including chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). Interestingly, CLL / SLL cells express PD-1, but normal B cells do not. Dr. Chang and colleagues wanted to learn more about the role of PD-1 in CLL / SLL biology.
Methods and Participants:
This study used blood samples from patients with CLL. Some patients were treatment-naïve, and others received BTK inhibitor therapy. The blood samples were analyzed by flow cytometry (what cells are present?), and then RNA sequencing analysis was performed on the flow-sorted cells (what genes are the cells expressing?).
Results:
- PD-1 expression occurs when CLL cells receive an activation signal either through the B-cell receptor (BCR) pathway or the toll-like receptor (TLR) pathway.
- If the BCR pathway growth signal is blocked by treatment with a BTK inhibitor (ibrutinib, acalabrutinib, zanubrutinib), PD-1 expression is also blocked.
- In treatment-naïve patients, approximately 10-85% of circulating CLL cells express PD-1.
- When patients with CLL started ibrutinib or acalabrutinib therapy, the percentage of cells expressing PD-1 dropped dramatically.
- While patients were responding to treatment, PD-1 was expressed in <10% of circulating CLL cells.
- The percentage of cells expressing PD-1 increased prior to clinical progression, and this was accompanied by increased expression of other genes involved in cellular growth and proliferation.
Conclusions:
CLL cells express PD-1 when they are actively growing. BTK inhibitors greatly reduce the number of CLL cells that express PD-1, and increased PD-1 expression may be an early sign of resistance to BTK inhibitor therapy. It’s hypothesized that the B-cell receptor (BCR) and other stimulating signals for B cells lead to increased PD-1 expression. This explains why BTKi inhibitors that block BCR result in lower PD-1 expression when they are active. While this research doesn’t have direct clinical implications yet, this type of research is fundamental to our understanding of the biology of CLL.
Links and Resources:
Dr. Chang’s CLL research is supported in part by a grant from CLL Society.
Watch the interview on the abstract here:
You can read the actual ASH abstract here: PD-1 Expression Identifies Proliferating Chronic Lymphocytic Leukemia Cells and Informs Response and Resistance to BTK Inhibitor Therapy
