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Case Reports
. 2000 Dec 4;192(11):1637-44.
doi: 10.1084/jem.192.11.1637.

Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of t cell-mediated vitiligo

C Yee  1 , J A Thompson, P Roche, D R Byrd, P P Lee, M Piepkorn, K Kenyon, M M Davis, S R Riddell, P D Greenberg
Affiliations
Case Reports

Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of t cell-mediated vitiligo

C Yee et al. J Exp Med. .

Abstract

Current strategies for the immunotherapy of melanoma include augmentation of the immune response to tumor antigens represented by melanosomal proteins such as tyrosinase, gp100, and MART-1. The possibility that intentional targeting of tumor antigens representing normal proteins can result in autoimmune toxicity has been postulated but never demonstrated previously in humans. In this study, we describe a patient with metastatic melanoma who developed inflammatory lesions circumscribing pigmented areas of skin after an infusion of MART-1-specific CD8(+) T cell clones. Analysis of the infiltrating lymphocytes in skin and tumor biopsies using T cell-specific peptide-major histocompatibility complex tetramers demonstrated a localized predominance of MART-1-specific CD8(+) T cells (>28% of all CD8 T cells) that was identical to the infused clones (as confirmed by sequencing of the complementarity-determining region 3). In contrast to skin biopsies obtained from the patient before T cell infusion, postinfusion biopsies demonstrated loss of MART-1 expression, evidence of melanocyte damage, and the complete absence of melanocytes in affected regions of the skin. This study provides, for the first time, direct evidence in humans that antigen-specific immunotherapy can target not only antigen-positive tumor cells in vivo but also normal tissues expressing the shared tumor antigen.

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Figures

Figure 1
Figure 1
Clinical appearance of inflammatory skin lesions after infusion of autologous MART-1–specific CD8+ CTL clones and 500,000 U/m2/d of IL-2. (A) Close-up of well-circumscribed erythematous papules surrounding pigmented lentiges and nevi on right anterior shoulder. (B) Close-up of vitiliginous bullae appearing in the previous site of raised pigmented nevus on the back.
Figure 1
Figure 1
Clinical appearance of inflammatory skin lesions after infusion of autologous MART-1–specific CD8+ CTL clones and 500,000 U/m2/d of IL-2. (A) Close-up of well-circumscribed erythematous papules surrounding pigmented lentiges and nevi on right anterior shoulder. (B) Close-up of vitiliginous bullae appearing in the previous site of raised pigmented nevus on the back.
Figure 2
Figure 2
Progression of inflammatory lesions appearing around pigmented areas of skin from days 5–7 after T cell infusion 3.
Figure 3
Figure 3
Immunohistochemical staining of inflammatory lesion from skin biopsy obtained on day 6. Hematoxylin and eosin stain demonstrates intense lymphocytic infiltrate in the dermal–epidermal junction in the area of melanocytic nevus. Immunohistochemical staining of the same section demonstrates a predominant population of CD4−CD8+ lymphocytes in infiltrate.
Figure 4
Figure 4
Characterization of lymphocytes harvested from skin biopsy obtained day 6 after CTL infusion 3 (left) and from tumor biopsy (right). Same skin sample as in Fig. 3. Flow cytometry analysis (left) using PE-conjugated M27 tetramer or an irrelevant (T369) tetramer and anti-CD8–FITC antibody demonstrates a population of MART-1–specific CTL clones representing >28% of the CD8+ lymphocyte population recovered from the skin biopsy. Flow cytometry analysis (right) of tumor biopsy demonstrates MART-1–specific CTL staining comprising >37% of CD8+ lymphocytes in tumor sample.
Figure 5
Figure 5
Preinfusion and postinfusion skin biopsies stained with hematoxylin and eosin (H&E) (top) or anti–MART-1 horseradish peroxidase antibody (bottom). In the preinfusion sample, melanized keratinocytes and melanocytes are present in the dermal–epidermal layer. Abundant expression of MART-1 antigen is seen in basal melanocytes. In the postinfusion sample, melanocytes are absent, but residual melanin is observed coating melanophages (black arrowheads) and within melanophages (white arrowheads). No MART-1 staining is seen.
Figure 5
Figure 5
Preinfusion and postinfusion skin biopsies stained with hematoxylin and eosin (H&E) (top) or anti–MART-1 horseradish peroxidase antibody (bottom). In the preinfusion sample, melanized keratinocytes and melanocytes are present in the dermal–epidermal layer. Abundant expression of MART-1 antigen is seen in basal melanocytes. In the postinfusion sample, melanocytes are absent, but residual melanin is observed coating melanophages (black arrowheads) and within melanophages (white arrowheads). No MART-1 staining is seen.
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