概要: 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.
Total RNA from formalin-fixed paraffin-embedded (FFPE) skin from healthy controls and CTCL patients was extracted with miRNeasy FFPE kit (Qiagen).
建库方案:
RNAseq libraries were prepared from Ribo-Zero mRNA-enriched material using KAPA Stranded RNA-Seq Library Preparation Kit (Illumina Platforms) (Kapa Biosystems, Wilmington, USA) and 10 cycles of PCR amplification.
测序信息
分子类型:
poly(A)+ RNA
库的片段类型:
PAIRED
库的链类型:
-; Forward
测序平台:
ILLUMINA
测序仪型号:
Illumina HiSeq 2500
链特异性:
Unspecific; Specific
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文章
Primary T Cells from Cutaneous T-cell Lymphoma Skin Explants Display an Exhausted Immune Checkpoint Profile.
Cancer immunology research . 2018-06-12 [PMID:
29895574]
