Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma
Katelyn T. Byrne, Anik L. Côté, Peisheng Zhang, Shannon M. Steinberg, Yanxia Guo, Rameeza Allie, Weijun Zhang, Marc S. Ernstoff, Edward J. Usherwood, Mary Jo Turk
Katelyn T. Byrne, Anik L. Côté, Peisheng Zhang, Shannon M. Steinberg, Yanxia Guo, Rameeza Allie, Weijun Zhang, Marc S. Ernstoff, Edward J. Usherwood, Mary Jo Turk
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Research Article Oncology

Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma

Abstract

A link between autoimmunity and improved antitumor immunity has long been recognized, although the exact mechanistic relationship between these two phenomena remains unclear. In the present study we have found that vitiligo, the autoimmune destruction of melanocytes, generates self antigen required for mounting persistent and protective memory CD8+ T cell responses to melanoma. Vitiligo developed in approximately 60% of mice that were depleted of regulatory CD4+ T cells and then subjected to surgical excision of large established B16 melanomas. Mice with vitiligo generated 10-fold larger populations of CD8+ memory T cells specific for shared melanoma/melanocyte antigens. CD8+ T cells in mice with vitiligo acquired phenotypic and functional characteristics of effector memory, suggesting that they were supported by ongoing antigen stimulation. Such responses were not generated in melanocyte-deficient mice, indicating a requirement for melanocyte destruction in maintaining CD8+ T cell immunity to melanoma. Vitiligo-associated memory CD8+ T cells provided durable tumor protection, were capable of mounting a rapid recall response to melanoma, and did not demonstrate phenotypic or functional signs of exhaustion even after many months of exposure to antigen. This work establishes melanocyte destruction as a key determinant of lasting melanoma-reactive immune responses, thus illustrating that immune-mediated destruction of normal tissues can perpetuate adaptive immune responses to cancer.

Authors

Katelyn T. Byrne, Anik L. Côté, Peisheng Zhang, Shannon M. Steinberg, Yanxia Guo, Rameeza Allie, Weijun Zhang, Marc S. Ernstoff, Edward J. Usherwood, Mary Jo Turk

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Figure 5

Melanoma-specific memory T cells are maintained in vitiligo-affected mice despite hyporesponsiveness to homeostatic cytokines.

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Melanoma-specific memory T cells are maintained in vitiligo-affected mic...
(A–C) Mice were treated as in Figure 1A. (A) 260 days after surgery, IFN-γ ELISPOT was performed on CD8+ T cells from pooled lymph nodes (5–8 mice/group), with peptide-pulsed EL4 cells as targets. Vitiligo was classified as described in Figure 1. Data represent average ± SD of 4 replicate wells. (B–D) Mice received 104 naive Thy1.1+ pmel cells 1 day prior to treatment as in Figure 1A. Symbols represent individual mice, and horizontal lines represent averages. (B) At various times following surgery, the proportion of pmel (Thy1.1+) cells among total CD8+ T cells in lymph nodes was assessed by flow cytometry. Data from unaffected and vitiligo-affected mice were statistically different (P < 0.05 by t test) at all time points except day 90. (C) 215 days following surgery, CD8+Thy1.1+CD44hi pmel cells were assessed for expression of phenotypic markers. Histograms depict data from representative lymph node samples. (D) Thirty days after surgery, CD8+ T cells were isolated from spleens of vitiligo-affected mice and cultured with IL-15 or IL-7, and the proportion of Thy1.1+CD44hi pmel cells undergoing at least 1 round of division (% Proliferated) was assessed by CFSE dilution. Host memory phenotype T cells (CD8+CD44hiThy1.1–) were analyzed as a positive control. Symbols represent single wells; the experiment was performed 3 times, with similar results. Statistically significant differences were assessed by t test, with *P < 0.05, **P < 0.01, and ***P < 0.001.