Single-cell proteomics reveal lesion-specific aberrant T cells and immunological profiles in mycosis fungoides.

Mycosis fungoides, a cutaneous T-cell lymphoma, is characterized by clonal proliferation of aberrant CD4+ T cells and an evolving tumor microenvironment. Immunological heterogeneity across lesion stages and its role in disease severity remain poorly defined. We investigated lesion-specific aberrant T cells and immune cells in mycosis fungoides skin lesions using mass cytometry, cross-validated with public single-cell RNA-sequencing data, and assessed their associations with clinical outcome. Aberrant CD4+CD7-CD26-CCR4hi T cells expressing high levels of PD-1, PD-L1, and OX-40 were enriched in tumor lesions but absent in patches. Aberrant PD-L1+ T cells exhibited central memory/effector memory phenotype, whereas aberrant PD-1+ T cells demonstrated a terminal effector phenotype. Tumor microenvironment analysis revealed increased frequencies of PD-L1+IgD- memory B cells, PD-L1+ regulatory T cells, PD-L1+NCR- type 3 innate lymphoid cells, and PD-1+CD4+/CD8+ T cells in tumors. Patches lacked innate lymphoid cells, memory B cells and naïve/central memory CD8+ T cells. Large cell transformation was associated with elevated frequencies of naïve B cells, PD-1+ monocytes, and PD-1+CD8+ central memory/effector memory T cells. High frequencies of PD-L1+ memory B cells, PD-1+ dendritic cell, and PD-1+ naïve CD4+ T cells correlated with shorter progression-free survival, whereas normal levels of PD-1+ transitional monocytes were associated with longer overall survival. Lesion-specific aberrant T cells and tumor microenvironment remodeling may drive mycosis fungoides severity and contribute to future immunotherapy.