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Striking Immunodominance Hierarchy of Naturally Occurring CD8⁺ and CD4⁺ T Cell Responses to Tumor Antigen NY-ESO-1¹

Heather Jackson^*, Nektaria Dimopoulos^*, Nicole A. Mifsud^*, Tsin Yee Tai^*, Qiyuan Chen^*, Suzanne Svobodova^*,, Judy Browning, Immanuel Luescher, Lisa Stockert, Lloyd J. Old, Ian D. Davis^*, Jonathan Cebon^* and Weisan Chen^2,*

^* Ludwig Institute for Cancer Research and Department of Pathology, Austin Health, Heidelberg, Victoria, Australia; Ludwig Institute for Cancer Research, Lausanne, Switzerland; and Ludwig Institute for Cancer Research, New York, NY 10021

Immunodominance has been well-demonstrated in many antiviral and antibacterial systems, but much less so in the setting of immune responses against cancer. Tumor Ag-specific CD8⁺ T cells keep cancer cells in check via immunosurveillance and shape tumor development through immunoediting. Because most tumor Ags are self Ags, the breadth and depth of antitumor immune responses have not been well-appreciated. To design and develop antitumor vaccines, it is important to understand the immunodominance hierarchy and its underlying mechanisms, and to identify the most immunodominant tumor Ag-specific T cells. We have comprehensively analyzed spontaneous cellular immune responses of one individual and show that multiple tumor Ags are targeted by the patient’s immune system, especially the "cancer-testis" tumor Ag NY-ESO-1. The pattern of anti-NY-ESO-1 T cell responses in this patient closely resembles the classical broad yet hierarchical antiviral immunity and was confirmed in a second subject.

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