Primary T Cells from Cutaneous T-cell Lymphoma Skin Explants Display an Exhausted Immune Checkpoint Profile.
Christiane Querfeld, Samantha Leung, Patricia L Myskowski, Shane A Curran, Debra A Goldman, Glenn Heller, Xiwei Wu, Sung Hee Kil, Sneh Sharma, Kathleen J Finn, Steven Horwitz, Alison Moskowitz, Babak Mehrara, Steven T Rosen, Allan C Halpern, James W Young
Author Information
Christiane Querfeld: Laboratory of Cellular Immunobiology, Immunology Program, Sloan Kettering Institute for Cancer Research, New York, New York. cquerfeld@coh.org.
Samantha Leung: Laboratory of Cellular Immunobiology, Immunology Program, Sloan Kettering Institute for Cancer Research, New York, New York.
Patricia L Myskowski: Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Shane A Curran: Laboratory of Cellular Immunobiology, Immunology Program, Sloan Kettering Institute for Cancer Research, New York, New York.
Debra A Goldman: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Glenn Heller: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Xiwei Wu: Beckman Research Institute, City of Hope, Duarte, California.
Sung Hee Kil: Beckman Research Institute, City of Hope, Duarte, California.
Sneh Sharma: Laboratory of Cellular Immunobiology, Immunology Program, Sloan Kettering Institute for Cancer Research, New York, New York.
Kathleen J Finn: Laboratory of Cellular Immunobiology, Immunology Program, Sloan Kettering Institute for Cancer Research, New York, New York.
Steven Horwitz: Weill Cornell Medical College, New York, New York.
Alison Moskowitz: Weill Cornell Medical College, New York, New York.
Babak Mehrara: Weill Cornell Medical College, New York, New York.
Steven T Rosen: Beckman Research Institute, City of Hope, Duarte, California.
Allan C Halpern: Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
James W Young: Laboratory of Cellular Immunobiology, Immunology Program, Sloan Kettering Institute for Cancer Research, New York, New York. ORCID
Cutaneous T-cell lymphoma (CTCL) develops from clonally expanded CD4 T cells in a background of chronic inflammation. Although dendritic cells (DCs) stimulate T cells and are present in skin, cutaneous T cells in CTCL do not respond with effective antitumor immunity. We evaluated primary T-cell and DC ��migr��s from epidermal and dermal explant cultures of skin biopsies from CTCL patients ( = 37) and healthy donors ( = 5). Compared with healthy skin, CD4 CTCL populations contained more T cells expressing PD-1, CTLA-4, and LAG-3. CD8 CTCL populations contained 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 ��migr��s 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 more checkpoint inhibition mRNA 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 isolated from the lesional skin of patients with CTCL, with increasing expression as the disease progresses. 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. .
