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 6

Protective post-surgical memory is only maintained in hosts with vitiligo.

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Protective post-surgical memory is only maintained in hosts with vitilig...
Mice were either primed as shown in Figure 1A or left untreated, stratified based on the development or lack of vitiligo 30–60 days later, and rechallenged with B16 melanoma. (A) Incidence of tumors inoculated i.d., 30 days after surgery. Anti-CD8 was administered 2 days prior to challenge and weekly thereafter. Data represent 6–22 mice/group, combined from 2 experiments. (B) Incidence of tumors inoculated i.v., 30 days after surgery. Lung tumor burden was assessed 21 days after challenge; symbols represent individual mice. (C) Incidence of tumors inoculated i.d., 60 days after surgery. Data represent 19–25 mice/group, combined from 3 experiments. (D and E) Mice received i.d. tumor challenge 30 days after surgery, and recall responses were assessed in draining lymph nodes 6 days later. (D) IFN-γ ELISPOT was performed on CD8+ T cells from pooled lymph nodes (6 mice/group), with peptide-pulsed EL4 cells or B16 cells as targets. Data represent mean ± SD of 4 replicate wells. (E) Mice received 104 Thy1.1+ pmel cells 1 day before priming, and the proportion of Thy1.1+ pmel cells among total CD8+ T cells was assessed by flow cytometry. Symbols represent individual mice, and horizontal lines represent averages. Data are combined from 2 experiments. Significance was determined by log-rank analysis (A and C) or t test (B, D, and E), with **P < 0.01, ***P < 0.001, and NS denoting P > 0.05. 3X and 10X indicate 3-fold and 10-fold increases, respectively.