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Implantation and Evaluation of Melanoma in the Murine Choroid via Optical Coherence Tomography
Published on: December 2, 2022
Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity
Douglas C Palmer1, Chi-Chao Chan, Luca Gattinoni
1National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. palmerd@mail.nih.gov
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 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.
Insights
Cancer immunotherapies targeting shared self-antigens can cause severe eye autoimmunity. Local steroid treatment mitigated this ocular side effect without compromising anti-tumor efficacy, suggesting careful antigen selection is crucial.
Area of Science:
- Immunology
- Oncology
- Ophthalmology
Background:
- Cancer immunotherapy effectively targets tumor antigens but can affect self-tissues.
- The impact of potent anti-tumor immune responses on normal tissues expressing shared antigens requires further investigation.
Purpose of the Study:
- To characterize the consequences of adoptive T cell therapy targeting melanoma/melanocyte antigens on ocular tissues.
- To investigate the mechanisms underlying therapy-induced ocular autoimmunity and explore mitigation strategies.
Main Methods:
- Adoptive transfer of ex vivo expanded melanoma/melanocyte-specific CD8+ T cells in a preclinical model.
- Assessment of tumor killing, ocular autoimmunity, MHC class I expression, and Interferon-gamma (IFN-γ) levels.
- Evaluation of the role of the IFN-γ receptor and the effect of local steroid administration.
Main Results:
- Effective tumor immunotherapy led to autoimmune destruction of ocular melanocytes.
- Ocular autoimmunity correlated with increased MHC class I expression and IFN-γ signaling.
- IFN-γ receptor on target tissues was essential for ocular autoimmunity development.
- Local high-dose steroids reduced ocular autoimmunity without impairing anti-tumor response.
Conclusions:
- Adoptive T cell therapy targeting shared self-antigens can induce significant ocular autoimmunity.
- IFN-γ signaling plays a critical role in mediating this off-target autoimmune effect.
- Targeting unique tumor antigens absent in critical tissues is essential for safe and effective cancer immunotherapy.
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