Elevated cholesterol uptake by T cells is a biomarker for the efficacy of immune checkpoint inhibitors in mouse models for triple negative breast cancer

Abstract

Abstract Predicting the outcome of cancer immunotherapy can help avoid the cost and side effects of ineffective treatment and help develop effective treatment strategies. T cells take up cholesterol during activation, which is necessary for their proliferation. However, there is no literature linking the uptake of cholesterol as a biomarker for T cell activation and less so as a biomarker for immune checkpoint inhibitor therapy (ICI). Our research group has developed a novel radioactive cholesterol analog called 18F-FNP-59, which can be used to measure the uptake of cholesterol in live cells and within living organisms. We hypothesize that elevated cholesterol influx in T cells of the tumor microenvironment is linked to T cell activation and predicts the success of cancer immunotherapy in triple negative breast cancer (TNBC) models. We found that the elevated uptake of exogenous labeled cholesterol analogs functions as a biomarker for T cell activation. When comparing ICI-responsive E0771 tumors to non-responsive AT3 tumors, we found that the uptake of a fluorescent cholesterol analog was significantly higher in the T cells of the ICI-responsive tumors both in vitro and in vivo. Using the 18F-FNP-59 compound, we found that the uptake of cholesterol by T cells was further enhanced in ICI-responding tumors that received anti-PD-1 treatment. These results suggest that the uptake of exogenous cholesterol analogs by tumor-infiltrating T cells may be able to predict T cell activation and the success of ICI therapy. In future studies, we will expand the tumor models and types of cancers that we observe. Additionally we will examine the relationship between T cell cholesterol trafficking and invasion of T cells into the tumor using imaging techniques.