Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity

Douglas C. Palmer, Chi Chao Chan, Luca Gattinoni, Claudia Wrzesinski, Chrystal M. Paulos, Christian S. Hinrichs, Daniel J. Powell, Christopher A. Klebanoff, Steven E. Finkelstein, Robert N. Fariss, Zhiya Yu, Robert B. Nussenblatt, Steven A. Rosenberg, Nicholas P. Restifo

Research output: Contribution to journalArticlepeer-review

Abstract

Nonmutated tissue differentiation antigens expressed by tumors are attractive targets for cancer immunotherapy, but the consequences of a highly effective antitumor immune response on self-tissue have not been fully characterized. We found that the infusion of ex vivo expanded adoptively transferred melanoma/ melanocyte-specific CD8+ T cells that mediated robust tumor killing also induced autoimmune destruction of melanocytes in the eye. This severe autoimmunity was associated with the upregulation of MHC class I molecules in the eye and high levels of IFN-γ derived from both adoptively transferred CD8+ T cells and host cells. Furthermore, ocular autoimmunity required the presence of the IFN-γ receptor on target tissues. Data compiled from >200 eyes and tumors in 10 independently performed experiments revealed a highly significant correlation (P < 0.0001) between the efficacy of tumor immunotherapy and the severity of ocular autoimmunity. Administration of high doses of steroids locally mitigated ocular autoimmunity without impairing the antitumor effect. These findings have particular importance for immunotherapies directed against self-antigens and highlight the need for targeting unique tumor antigens not expressed in critical tissues.

Original languageEnglish (US)
Pages (from-to)8061-8066
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number23
DOIs
StatePublished - Jun 10 2008
Externally publishedYes

Keywords

  • Adoptive cell transfer
  • Cancer
  • IFN-γ
  • Immunotherapy
  • Vaccine

ASJC Scopus subject areas

  • General

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