CD5 Expression in CTCL and Its Implications for Anti-CD5 CAR T-Cell Therapy

Cutaneous T-Cell Lymphomas (CTCL) are a heterogenous group of T-cell malignancies in the skin and have poor treatment outcomes in advanced stages. CD5, a surface glycoprotein expressed on most mature T cells, has emerged as a promising target for chimeric antigen receptor (CAR) T-cell therapy in systemic T-cell lymphomas. However, its expression profile in CTCL and relevance for targeted therapy remain unclear. Notably, in CTCL, the cell surface expression of receptors, such as CD7 and CD26, tends to become downregulated on the surfaces of malignant T cells In this study, we analyzed single-cell RNA sequencing (scRNA-seq) data from patients at two institutions with mycosis fungoides (MF), the most common subtype of CTCL with a predominantly CD4 phenotype. We utilized 5 patch/plaque MF skin biopsies (majority from early-stage patients), 8 MF tumor biopsies (all from advanced-stage patients), and 8 healthy control biopsies to evaluate lesion-specific <i>CD5</i> gene expression on CD4 T cells. We found that <i>CD5</i> was significantly increased in malignant MF CD4 T cells compared to healthy control CD4 T cells (21.1% of MF CD4 T cells expressed <i>CD5</i> vs. 5.2% of healthy control CD4 T cells, respectively). In subgroup analysis, patch/plaque stage MF biopsies showed higher expression of <i>CD5</i> in CD4 T cells than tumor stage MF biopsies. Notably, 94.3% of malignant CD4⁺ T cells in tumor stage MF lesions exhibited complete <i>CD5</i> loss compared to only 76.6% in patch-plaque MF lesions, suggesting antigen escape in tumor stage disease. These findings demonstrate that <i>CD5</i> expression in CTCL is dynamic and varies based on lesion type. Our work suggests CD5 may be a viable therapeutic target in MF with patch/plaque presentations but may not be as effective in advanced stages of MF with tumor presentations. This work informs <i>CD5</i> gene expression in MF based on clinical lesion type and further information is needed to clarify clinical implications as a future therapeutic target.