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

免疫疗法 三阴性乳腺癌 癌症研究 乳腺癌 癌症 癌症免疫疗法 免疫系统 胆固醇 肿瘤微环境 生物标志物 T细胞 免疫检查点 体内 医学 生物 内科学 免疫学 生物化学 生物技术
作者
Nicholas G. Ciavattone,Jenny Guan,Alex P. Farfel,Timothy J. Desmond,Benjamin L. Viglianti,Peter J. H. Scott,Allen F. Brooks,Gary D. Luker
标识
DOI:10.1101/2023.10.02.560577
摘要

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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