Melanocyte Destruction after Antigen-Specific Immunotherapy of Melanoma

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.

A single-nucleotide polymorphism in the gene encoding lymphoid protein tyrosine phosphatase (PTPN22) confers susceptibility to generalised vitiligo

“…[7][8][9] Melanocyte-specific CTLs have also been identified in patients with melanoma where vitiligo has occurred during immunotherapy and the adoptive transfer of melanoma antigen-specific CTLs may be associated with the regression of melanoma metastases and the appearance of vitiligo. [30][31][32] Experiments in murine models have also demonstrated that CTLs to melanocytic antigens can cause the destruction of pigment cells leading to vitiligo-like fur depigmentation. 33 These observations provide evidence of T-cellmediated vitiligo in both humans and mice and suggest that unregulated T-cell activity may contribute to the development of the disease.…”

Qualitative difference between the cytotoxic T lymphocyte responses to melanocyte antigens in melanoma and vitiligo

“…Similarities exist between the autoimmunity observed in vitiligo and the tumor immunity observed in melanoma immuno-surveillance, as CTL directed to self antigens shared by normal melanocytes and melanoma cells are found in both conditions and imply a breakdown of tolerance [5][6][7][8][9][10]. However, the resulting immune reaction is the opposite: In vitiligo, natural immune tolerance is overridden such that the host immune system can orchestrate melanocyte destruction, whereas in melanoma, an immune effector function of potential benefit to the host, i.e.…”

Melanoma antigen expression in serial fine-needle aspiration samples in patients with metastatic malignant melanoma participating in immunotherapy clinical trials

“…In a report by Yee et al, one patient with MMM developed inflammatory lesions circumscribing pigmented areas of skin after an infusion of MART-1 specific CD8(ϩ) T cell clones. 22 In contrast with 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. 22 They concluded that antigen specific immunotherapy could target both antigen positive tumor cells as well as normal tissues expressing the shared tumor antigen, in this case, MART-1.…”

“…22 In contrast with 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. 22 They concluded that antigen specific immunotherapy could target both antigen positive tumor cells as well as normal tissues expressing the shared tumor antigen, in this case, MART-1. 22 In another study, a comparative analysis of repeated biopsies of the same metastatic lesions over a 9-month period showed a gradual loss of MART-1/ MelanA expression in 4 of 5 patients with tumor progression.…”

“…22 They concluded that antigen specific immunotherapy could target both antigen positive tumor cells as well as normal tissues expressing the shared tumor antigen, in this case, MART-1. 22 In another study, a comparative analysis of repeated biopsies of the same metastatic lesions over a 9-month period showed a gradual loss of MART-1/ MelanA expression in 4 of 5 patients with tumor progression. 23 Thus, it would appear that the use of antibodies to MAA for diagnostic purposes would possibly be compromised in patients participating in these protocols.…”