Lo et al. found that in melanocytes, MITF mediates upregulation of PD-L1 by binding to an enhancer, inducing high baseline PD-L1 that is further upregulated upon exposure to UVR. This mechanism has a tolerogenic effect, protecting melanocytes from immune-mediated elimination, even after the accumulation of UV-induced mutations. While this mechanism did not appear to play a major role in immune-hot melanomas with high IFNγ expression, it did show an effect in less infiltrated melanomas, and could contribute to their development.
ABSTRACT: UV radiation (UVR) drives high mutational burdens, yet precursor melanocytes accumulate these mutations without triggering immune clearance. Here, we investigated whether melanocyte-intrinsic transcriptional program(s) underlie immune tolerance to mutations resulting from UVR exposure. In primary human melanocytes, expression of PD-L1 (CD274) was dependent on microphthalmia-associated transcription factor (MITF), a crucial regulator of melanocyte development and an intermediate in the UV-tanning pathway. MITF directly activated PD-L1 transcription by binding a conserved upstream enhancer containing functional E-box elements. MITF determined both baseline melanocytic PD-L1 expression in healthy skin and its induction following UVR, independent of interferon signaling. Melanocyte-restricted Pd-l1 deletion in mice triggered CD8(+) T cell infiltration and depigmentation after long-term UVB exposure, recapitulating features of human vitiligo. PD-L1-deficient human induced pluripotent stem cell (iPSC)-derived melanocytes underwent increased apoptosis and were more susceptible than PD-L1-intact melanocytes to gp100-specific CD8(+) T cell killing. Thus, a melanocyte-intrinsic MITF-PD-L1 tolerance program protects melanocytes from autoimmune destruction, potentially facilitating early immune evasion during melanoma development and conversely underlying the responsiveness of melanoma to PD-1/PD-L1 blockade.
Author Info: (1) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, Beth
Author Info: (1) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (2) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (3) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (4) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (5) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan. (6) Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. (7) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (8) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (9) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (10) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Stomatology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong, China. (11) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (12) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; HCEMM-SU Translational Dermatology Research Group, Semmelweis University, Budapest 1085, Hungary; Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary; Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Budapest 1085, Hungary; MTA-SE Lendlet "Momentum" Dermatology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest 1085, Hungary. (13) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (14) Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA; Dermatology Service, San Francisco Veterans Administration Health Care System, San Francisco, CA 94121, USA. (15) Lautenberg Center for Immunology and Cancer Research, The Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel; Center for Melanoma and Cancer Immunotherapy, Sharett Institute of Oncology, Jerusalem 91120, Israel; Hadassah Cancer Research Institute, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel. (16) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (17) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (18) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland. (19) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, University of Utah, Salt Lake City, UT 84132, USA. (20) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (21) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (22) IStem, CECS, Corbeil-Essonnes 91100, France. (23) Universit Paris-Saclay, Universit d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (24) Universit Paris-Saclay, Universit d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (25) Universit Paris-Saclay, Universit d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (26) Universit Paris-Saclay, Universit d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA. (28) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02142, USA. (29) Mass General Brigham Cancer Institute, Boston, MA 02114, USA. (30) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA. (31) Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. (32) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA. (33) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (34) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Parker Institute of Cancer Immunotherapy, San Francisco, CA 94129, USA. (35) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Universit Paris-Saclay, Universit d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. Electronic address: jeallouche@gmail.com. (36) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. Electronic address: dfisher3@mgh.harvard.edu.
