Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity.
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 up-regulation of MHC class I molecules in the eye and high levels of IFN-gamma derived from both adoptively transferred CD8+ T cells and host cells. Furthermore, ocular autoimmunity required the presence of the IFN-gamma 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.
National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. palmerd@mail.nih.gov
Douglas C
DC
Palmer
Chi-Chao
CC
Chan
Luca
L
Gattinoni
Claudia
C
Wrzesinski
Chrystal M
CM
Paulos
Christian S
CS
Hinrichs
Daniel J
DJ
Powell
Christopher A
CA
Klebanoff
Steven E
SE
Finkelstein
Robert N
RN
Fariss
Zhiya
Z
Yu
Robert B
RB
Nussenblatt
Steven A
SA
Rosenberg
Nicholas P
NP
Restifo
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005123:Eye / Q000276:immunology* / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D017471:Receptors, Interferon / Q000276:immunology; D015854:Up-Regulation; D000096743:Interferon gamma Receptor
D000951:Antigens, Neoplasm; D015395:Histocompatibility Antigens Class I; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor