GSE113113
Primary T cells from cutaneous T-cell lymphoma skin explants display an exhausted  immune checkpoint profile
Cutaneous T-cell lymphoma (CTCL) develops from clonally expanded CD4+ T cells in a  background of chronic inflammation. Dendritic cells (DCs) are potent T-cell stimulators; yet  despite DCs' extensive presence in skin, cutaneous T cells in CTCL do not respond with  effective anti-tumor immunity. We evaluated primary T-cell and DC émigrés from epidermal and  dermal explant cultures of skin biopsies from CTCL patients (n = 37) and healthy donors (n = 5).  Compared with healthy skin, CD4+ CTCL populations contained more T cells expressing PD-1,  CTLA-4, and LAG-3; and CD8+ CTCL populations comprised more T cells expressing CTLA-4  and LAG-3. CTCL populations also contained more T cells expressing the inducible T-cell  costimulator (ICOS), a marker of T-cell activation. DC émigrés from healthy or CTCL skin  biopsies expressed PD-L1, indicating that maturation during migration resulted in PD-L1  expression irrespective of disease. Most T cells did not express PD-L1. Using skin samples  from 49 additional CTCL patients for an unsupervised analysis of genome-wide mRNA  expression profiles corroborated that advanced T3/T4 stage samples expressed higher levels of  checkpoint inhibition genes compared with T1/T2 stage patients or healthy controls. Exhaustion  of activated T cells is therefore a hallmark of both CD4+ and CD8+ T cells directly isolated from  the lesional skin of patients with CTCL, with a continuum of increasing expression in more  advanced stages of disease. These results justify identification of antigens driving T-cell  exhaustion and the evaluation of immune checkpoint inhibition to reverse T-cell exhaustion  earlier in the treatment of CTCL. Overall design: RNA-seq correlated with tumor stages