Researchers at The University of Texas MD Anderson Cancer Center have identified CD40 overexpression as a potential prognostic biomarker in angioimmunoblastic T-cell lymphoma (AITL), a rare subtype of non-Hodgkin lymphoma that is difficult to diagnose and treat. The results of their study were presented at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 555).
Background and Study Details
AITL arises from T follicular helper (TFH) cells and impacts the lymph nodes, bone marrow, and in some cases, the liver or spleen. Its complex microenvironment is primarily composed of immune cells, with neoplastic TFH cells typically accounting for only 10% to 30% of the infiltrate. This heterogeneous composition often results in delayed or incorrect diagnoses and poor treatment outcomes.
The research team, led by Francisco Vega, MD, PhD, employed single-cell RNA sequencing alongside COMET, a sequential immunofluorescence platform, to analyze 14 AITL lymph nodes and 3 reactive lymph nodes. This combined approach enabled precise mapping of gene-expression programs and cell-type distribution within the tumor environment.
The investigators found that, in a subset of cases, neoplastic TFH cells exhibited increased expression of genes more typically associated with regulatory T cells, including FOXP3, suggesting that malignant cells may adopt a T follicular–regulatory program. This adaptability may partly explain the diagnostic ambiguity and clinical challenges observed in AITL, marking the first reported description of this phenotype.
A second major finding was the consistent elevation of CD40 expression across two distinct microenvironmental patterns and in patient-derived xenograft models. Because no prognostic biomarkers currently exist for AITL, CD40 overexpression may offer a new tool for assessing patient risk and monitoring disease response.
Presenting author Tania Sainz emphasized the clinical importance of these findings: “The discovery of CD40 overexpression as a potential biomarker gives us a new lens to assess patient risk and opens the door to therapeutic strategies that could improve outcomes for this challenging disease, especially since no biomarkers to predict [overall survival] are currently available.”
Future Directions
According to the study authors, more work is needed to determine the frequency of the newly described T follicular–regulatory phenotype, its clinicopathologic features, and whether CD40 levels can reliably stratify risk or predict treatment response. Researchers also plan to explore whether CD40-targeted therapies may hold promise as a potential therapeutic strategy.
Disclosure: The study was funded by MD Anderson. For full disclosures of the study authors, visit hematology.org.
