Editor's Note: The 66th American Society of Hematology (ASH) Annual Meeting, held in San Diego from December 7–10, 2024, brought together global hematology experts to discuss the latest research advancements. Among the noteworthy contributions, Dr. Qingxiao Song’s team from the Hematology Medical Center of The Second Affiliated Hospital of Army Medical University (Xinqiao Hospital) had three studies selected (O263, P3391, P4777), with two of them earning ASH Abstract Achievement Awards. These studies offer new insights and therapeutic possibilities for chronic graft-versus-host disease (cGVHD). Hematology Frontier invited Dr. Qingxiao Song for an in-depth analysis of these groundbreaking studies.

Award-Winning Abstracts

• Targeting the Hypoxic Microenvironment in Cutaneous Chronic Graft-Versus-Host Disease through PI3Kδ Inhibition Abstract O263

Dr. Qingxiao Song: Chronic graft-versus-host disease (cGVHD) is one of the most common post-transplant complications, significantly impacting patients’ long-term quality of life. As such, it remains a key focus of clinical attention. The pathology of cGVHD is complex, involving chronic inflammation and fibrosis. Once the disease progresses to the end-stage fibrotic phase, anti-inflammatory treatments alone are often insufficient to reverse the pathological changes.

Clinically, the major challenge lies in effectively preventing and reversing the fibrotic progression of cGVHD. Currently, glucocorticoids are the first-line treatment for cGVHD. However, around 50% of patients show poor responses to steroid therapy, necessitating second-line treatment options. While no unified standard exists for second-line therapies, various targeted agents, including JAK inhibitors, ROCK2 inhibitors, BTK inhibitors, and CSF1R inhibitors, have shown promise by modulating different immune cell types such as T cells, B cells, and macrophages.

Second-line treatments often combine glucocorticoids with other targeted therapies, with the specific choice of agents guided by clinical judgment and the patient’s condition. However, the complexity of cGVHD lies in its ability to affect multiple organs, each with distinct pathological characteristics. This makes the precise selection of therapeutic targets a critical factor in successful treatment.

Our team is dedicated to advancing cGVHD research, particularly in understanding the immune microenvironment and organ-specific pathogenesis. By identifying new therapeutic targets, we aim to refine individualized and precision treatment strategies, ultimately offering more effective solutions for patients.

Our study, Abstract O263, focuses on skin cGVHD, combining preclinical mouse models with skin biopsy samples from cGVHD patients to investigate its pathogenesis.

Key Findings:

• Hypoxic Microenvironment: We discovered that skin cGVHD is characterized by a hypoxic microenvironment, which promotes the activation of the PI3K/AKT signaling pathway in infiltrating immune cells.
• Pathological Th2 Cells: Under hypoxia, T cells in the skin adopt a pathological Th2 phenotype, secreting elevated levels of IL-13, which exacerbates hypoxia.
• Pro-Inflammatory Macrophages: Hypoxia also drives macrophages toward a pro-inflammatory and pro-fibrotic phenotype, creating a vicious cycle that perpetuates fibrosis.

Mechanistic Insights:

We identified the HIF1α-PI3Kδ-IL-13 axis as a critical regulator of fibrosis in skin cGVHD. Targeting key molecules in this pathway—HIF1α, PI3Kδ, or IL-13—demonstrated significant efficacy in preventing and reversing fibrosis in preclinical models.

Clinical Implications:

PI3Kδ inhibitors, already FDA-approved for lymphoma treatment, may offer a new therapeutic avenue for skin cGVHD fibrosis, accelerating the translational application of these findings.

Dr. Qingxiao Song: This year’s ASH meeting showcased notable progress in cGVHD research, with two studies standing out:

1. Post-Transplant Cyclophosphamide (PTCy): PTCy demonstrated exceptional efficacy in preventing and treating cGVHD. By selectively eliminating alloreactive T cells while preserving regulatory T cells, PTCy significantly reduced cGVHD incidence, even among high-risk patients. This advancement not only improves quality of life but also reduces reliance on post-transplant immunosuppressants, marking a major breakthrough in cGVHD prevention.
2. Extracorporeal Photopheresis (ECP): New insights into ECP’s mechanism revealed its ability to deactivate T cells through ultraviolet irradiation, followed by macrophage-mediated T-cell suppression. This approach effectively mitigates inflammation and has shown promising results in cGVHD treatment, although larger clinical trials are needed to validate its efficacy.

Additional Highlights from Professor Song’s Team

• Tissue-Resident Double Negative T Cells in Oral cGVHD Abstract P3391: This study revealed that tissue-resident double-negative T cells mediate salivary gland damage in chronic oral cGVHD, shedding light on potential therapeutic targets.
• EZH2 Inhibition in cGVHD Abstract P4777: Targeting EZH2 alleviated cGVHD by modulating lipid metabolism reprogramming and senescence in neutrophils, offering a novel approach to treatment.

About Dr. Qingxiao Song

Position:

• Researcher, Hematology Medical Center, Second Affiliated Hospital of Army Medical University (Xinqiao Hospital)

Academic Roles:

• Member, Chongqing Physician Association Hematology Branch
• Member, American Society of Hematology (ASH)
• Editorial Board Member, Blood & Genomics

Research Focus:

Professor Song specializes in basic and translational research on hematopoietic stem cell transplantation. Her work has been supported by grants such as the “New Chongqing Talent Program” and has been published in leading journals including Blood, Journal of Clinical Investigation, Nature Communications, and PNAS, with numerous first and corresponding authorships.