Expression and prognostic value of FKBP51 in Hodgkin lymphoma

Silvia Varricchio¹Simona Romano¹Daniela Russo¹Antonio Travaglino²Rosaria Cappiello¹Mariarosaria Cervasio¹Gennaro Ilardi¹Laura Marrone¹Fabrizio Pane¹Marco Picardi¹Marcello Persico¹Elena Vigliar¹Gennaro Acanfora¹Maria Fiammetta Romano^1*Massimo Mascolo¹

• ¹University of Naples Federico II, Naples, Italy
• ²University of Insubria, Varese, Lombardia, Italy

Background: Hodgkin lymphoma (HL) is characterized by rare Hodgkin/Reed-Sternberg (H/RS) cells surrounded by a predominant immune infiltrate that shapes tumor biology and influences prognosis. FKBP51, an immunophilin and NF-κB/Akt modulator, is implicated in cancer progression, but its role within the HL tumor microenvironment (TME) remains unclear. Methods: We retrospectively analyzed 103 HL cases by immunohistochemistry for FKBP51, Bcl2, and immune subsets (CD4, CD8, CD68, CD163), with quantitative PCR of FKBP5, TRAF2, PCNA, XIAP, and BCL2 in 36 cases. Spatial immune architecture was assessed morphologically and via image analysis, with a focus on CD4 T-cell rosettes. Prognostic associations were evaluated through multivariate analyses. Results: FKBP51 was detected in both H/RS cells and infiltrating lymphocytes. While nuclear FKBP51 in H/RS cells lacked prognostic significance, FKBP51 expression in the TME correlated with adverse outcomes and remained an independent prognostic factor. CD4 T cells were the predominant immune cell subset and the main FKBP51-positive population. However, it was the density of tumor-associated macrophages (TAMs), rather than CD4 T-cell density, that held prognostic significance. CD4 T cells frequently formed rosette-like structures around H/RS cells, a spatial organization associated with the highest FKBP51 scores and unfavorable prognosis. CD8 T cells were less abundant, increased in advanced stages along with TAMs, and exhibited limited FKBP51 expression. Gene expression analysis showed FKBP51 correlation with proliferative and anti-apoptotic transcripts (PCNA, TRAF2, XIAP), supporting a protumor, NF-κB-driven microenvironment. Conclusions: FKBP51 expression in CD4 tumor-infiltrating lymphocytes, rather than tumor cells, defines a protumor TME that supports H/RS cell survival. Spatial immune architecture, particularly CD4 rosettes and TAM density, holds prognostic relevance in HL. FKBP51 may serve as a biomarker for risk stratification.