Interferon-gamma PET Imaging as a Predictive Tool for Monitoring Response to Tumor Immunotherapy

Interferon-gamma (IFN-gamma) is an attractive target for imaging active anti-tumor immunity due to its function in the T cell signaling axis. Here we test an IFN-gamma immuno-positron emission tomography (immunoPET) probe for its capacity to identify adaptive immunotherapy (ITx) response after HER2/neu vaccination in both spontaneous salivary and orthotopic neu+ mouse mammary tumors. IFN-gamma immunoPET detected elevated cytokine levels in situ post-vaccination, which inversely correlated with tumor growth rate, an indicator of response to therapy. In a model of induced T cell anergy where CD8 T cells infiltrate the tumor, but upregulate PD-1, IFN-gamma tracer uptake was equivalent to isotype control, illustrating a lack of anti-tumor T cell activity. The IFN-gamma immunoPET tracer detected IFN-gamma protein sequestered on the surface of tumor cells, likely in complex with the IFN-gamma receptor, which may explain imaging localization of this soluble factor in vivo. Collectively, we find that the activation status of cytotoxic T cells is annotated by IFN-gamma immunoPET, with reduced off-target binding to secondary lymphoid tissues compared to imaging total CD3+ tumor infiltrating lymphocytes. Targeting of soluble cytokines such as IFN-gamma by PET imaging may provide valuable non-invasive insight into the function of immune cells in situ.

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