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bioRxiv · 10.1101/2023.10.02.560577

Predicting efficacy of immunotherapy in mice with triple negative breast cancer using a cholesterol PET radiotracer

Ciavattone, N. G.·Guan, J.·Farfel, A.·Desmond, T.·Viglianti, B. L.·Scott, P. J.·Brooks, A. F.·Luker, G. D.
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Abstract

Predicting the response to cancer immunotherapy remains an unmet challenge in triple-negative breast cancer (TNBC) and other malignancies. T cells, the major target of current checkpoint inhibitor immunotherapies, accumulate cholesterol during activation to support proliferation and signaling. The requirement of cholesterol for anti-tumor functions of T cells led us to hypothesize that quantifying cellular accumulation of this molecule could distinguish successful from ineffective checkpoint immunotherapy. To analyze accumulation of cholesterol by T cells in the immune microenvironment of breast cancer, we leveraged a novel positron emission tomography (PET) radiotracer, FNP-59. FNP-59 is an analog of cholesterol that our group has validated as an imaging biomarker for cholesterol uptake in pre-clinical models and initial human studies. In immunocompetent mouse models of TNBC, we found that elevated uptake of exogenous labeled cholesterol analogs functions as a marker for T cell activation. When comparing immune checkpoint inhibitor (ICI)-responsive EO771 tumors to non-responsive AT-3 tumors, we found significantly higher uptake of a fluorescent cholesterol analog in T cells of the ICI-responsive tumors both in vitro and in vivo. Using the FNP-59 radiotracer, we discovered that accumulation of cholesterol by T cells increased further in ICI-responding tumors that received ant-PD-1 checkpoint immunotherapy. We verified these data by mining single cell sequencing data from patients with TNBC. Patients with tumors containing cycling T cells showed gene expression signatures of cholesterol uptake and trafficking. These results suggest that uptake of exogenous cholesterol analogs by tumor-infiltrating T cells predict T cell activation and success of ICI therapy.

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Ciavattone, N. G., Guan, J., Farfel, A., Desmond, T., Viglianti, B. L., Scott, P. J., Brooks, A. F., Luker, G. D.. 2023-10-03. Predicting efficacy of immunotherapy in mice with triple negative breast cancer using a cholesterol PET radiotracer. https://doi.org/10.1101/2023.10.02.560577

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