A link between tumor immunity and autoimmunity has been recognized for over 30 years, although the exact relationship between these two phenomena has remained evasive. Herein we provide compelling new data establishing that melanocyte destruction is required for the maintenance of CD8 memory T cell responses to melanoma. We show that, following depletion of regulatory T cells and surgical excision of established melanomas, spontaneous vitiligo maintains melanoma/melanocyte Ag-specific memory T cells that do not become functionally exhausted, and provide long-lived tumor protection. These studies establish a causal relationship between autoimmunity and long-lived anti-tumor immunity. It is now crucial to define the mechanisms underlying these long-lived T cell responses to cancer. We hypothesize that autoimmune disease provides a host environment that is uniquely capable of perpetuating T cell responses to tumor/self antigens;and that tissue-specific autoimmunity is required for the durable efficacy of tumor immunotherapies that target self-antigens. Our first Specific Aim will be to determine the autoimmune requirements for maintaining protective CD8 T cell responses to melanoma/melanocyte antigens. We will use various approaches to release melanocyte antigens, kill melanocytes, and induce autoimmune vitiligo, with a goal of restoring functional memory T cell responses against melanoma. Studies will employ B16 melanoma and the novel BrafV600E/Pten-/- model of inducible metastatic melanoma, which we have recently established on a C57BL/6 background. This work will reveal key mechanisms driving T cell memory to tumor/self antigens, while establishing a new paradigm for the treatment of melanoma. Next, Specific Aim 2 will determine how recently primed effector T cells and skin-homing/resident memory T cells contribute to tumor immunity in hosts with vitiligo. These studies will investigate if na?ve T cells primed by autoimmune melanocyte destruction become fully functional effectors that are capable of contributing to melanoma destruction. Experiments will also address how T cell access to depigmenting skin and draining lymph nodes governs the establishment of memory and long-lived protection against melanoma. This work is expected to fill a major void in our understanding of how tumor/self-reactive T cells efficiently originate, localize, and sustain themselves.)Finally, Specific Aim 3 will determine if the long-term effectiveness of CD8 and CD4 adoptive T cell therapies is dependent on the host's ability to develop vitiligo. The BrafV600E/Pten-/- melanoma model will be used to model immunotherapy in combination with molecularly- targeted BrafV600E inhibition. These studies will for the first time reveal the nature of the relationship between autoimmunity and memory CD4 T cell responses to cancer. In summary, this work will provide an in-depth and transformative look at previously unappreciated factors underlying enhanced tumor immunity in hosts with autoimmunity, leading to innovative new immunotherapy strategies for cancers of nonessential organs.

Public Health Relevance

This research is aimed at understanding immune responses to cancer and how they can be improved by autoimmune responses to normal tissues. These studies focus on the development of new therapies for cancer, and on determining why current therapies have (or lack) effectiveness, therefore they have broad relevance for public health.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA120777-06A1
Application #
8371848
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
2006-07-01
Project End
2017-04-30
Budget Start
2012-07-01
Budget End
2013-04-30
Support Year
6
Fiscal Year
2012
Total Cost
$213,666
Indirect Cost
$80,954
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Byrne, Katelyn T; Zhang, Peisheng; Steinberg, Shannon M et al. (2014) Autoimmune vitiligo does not require the ongoing priming of naive CD8 T cells for disease progression or associated protection against melanoma. J Immunol 192:1433-9
Steinberg, Shannon M; Zhang, Peisheng; Malik, Brian T et al. (2014) BRAF inhibition alleviates immune suppression in murine autochthonous melanoma. Cancer Immunol Res 2:1044-50
Jenkins, Molly H; Steinberg, Shannon M; Alexander, Matthew P et al. (2014) Multiple murine BRaf(V600E) melanoma cell lines with sensitivity to PLX4032. Pigment Cell Melanoma Res 27:495-501
Baird, Jason R; Byrne, Katelyn T; Lizotte, Patrick H et al. (2013) Immune-mediated regression of established B16F10 melanoma by intratumoral injection of attenuated Toxoplasma gondii protects against rechallenge. J Immunol 190:469-78
Byrne, Katelyn T; Cote, Anik L; Zhang, Peisheng et al. (2011) Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma. J Clin Invest 121:1797-809
Byrne, Katelyn T; Turk, Mary Jo (2011) New perspectives on the role of vitiligo in immune responses to melanoma. Oncotarget 2:684-94
Cote, Anik L; Byrne, Katelyn T; Steinberg, Shannon M et al. (2011) Protective CD8 memory T cell responses to mouse melanoma are generated in the absence of CD4 T cell help. PLoS One 6:e26491
Cote, Anik L; Zhang, Peisheng; O'Sullivan, Jeremy A et al. (2011) Stimulation of the glucocorticoid-induced TNF receptor family-related receptor on CD8 T cells induces protective and high-avidity T cell responses to tumor-specific antigens. J Immunol 186:275-83
Nesbeth, Yolanda; Scarlett, Uciane; Cubillos-Ruiz, Juan et al. (2009) CCL5-mediated endogenous antitumor immunity elicited by adoptively transferred lymphocytes and dendritic cell depletion. Cancer Res 69:6331-8
Cote, Anik L; Usherwood, Edward J; Turk, Mary Jo (2008) Tumor-specific T-cell memory: clearing the regulatory T-cell hurdle. Cancer Res 68:1614-7

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