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Modulating cholesterol metabolism can improve CD8 + T-cell-mediated immunity against tumours; genetic or pharmacological inhibition of the cholesterol esterification enzyme ACAT1 led to higher plasma membrane cholesterol levels, better T-cell receptor clustering and signalling, improved immunological synapse maturation, and enhanced antitumour activity in mice. T cell antitumour activity boosted This study reports a new approach to cancer immunotherapy through the modulation of T cell cholesterol metabolism. Chenqi Xu and colleagues demonstrate that inhibition of the cellular cholesterol esterification pathway in mice, either by genetic ablation or by pharmacological inhibition of acetyl-CoA acetyltransferase 1 (ACAT1) and ACAT2, increases plasma membrane cholesterol levels, T-cell receptor clustering and signalling, and significantly potentiates the antitumour response of CD8 + T cells in mice. To test the potential of ACAT1 as a drug target for cancer immunotherapy, the authors treated melanoma-bearing mice with avasimibe, an ACAT inhibitor that has been used to treat atherosclerosis in clinical trials. An antitumour effect was observed and a combination of avasimibe and anti-PD-1 antibody was more effective than either alone. CD8 + T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment 1 , 2 , 3 , 4 . Reactivating the cytotoxicity of CD8 + T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8 + T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme 5 , led to potentiated effector function and enhanced proliferation of CD8 + but not CD4 + T cells. This is due to the increase in the plasma membrane cholesterol level of CD8 + T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8 + T cells were better than wild-type CD8 + T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile 6 , 7 , to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.

CD8^sup +^ T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment1-4. Reactivating the cytotoxicity of CD8^sup +^ T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8^sup +^ T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme5, led to potentiated effector function and enhanced proliferation of CD8^sup +^ but not CD4^sup +^ T cells. This is due to the increase in the plasma membrane cholesterol level of CD8^sup +^ T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8^sup +^ T cells were better than wild-type CD8^sup +^ T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile6,7, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.

Background A high quality decision requires that patients who meet clinical criteria for surgery are informed about the options (including non-surgical alternatives) and receive treatments that match their goals. The aim of this study was to evaluate the psychometric properties and clinical sensibility of a patient self report instrument, to measure the quality of decisions about total joint replacement for knee or hip osteoarthritis. Methods The performance of the Hip/Knee Osteoarthritis Decision Quality Instrument (HK-DQI) was evaluated in two samples: (1) a cross-sectional mail survey with 489 patients and 77 providers (study 1); and (2) a randomized controlled trial of a patient decision aid with 138 osteoarthritis patients considering total joint replacement (study 2). The HK-DQI results in two scores. Knowledge items are summed to create a total knowledge score, and a set of goals and concerns are used in a logistic regression model to develop a concordance score. The concordance score measures the proportion of patients whose treatment matched their goals. Hypotheses related to acceptability, feasibility, reliability and validity of the knowledge and concordance scores were examined. Results In study 1, the HK-DQI was completed by 382 patients (79%) and 45 providers (58%), and in study 2 by 127 patients (92%), with low rates of missing data. The DQI-knowledge score was reproducible (ICC = 0.81) and demonstrated discriminant validity (68% decision aid vs. 54% control, and 78% providers vs. 61% patients) and content validity. The concordance score demonstrated predictive validity, as patients whose treatments were concordant with their goals had more confidence and less regret with their decision compared to those who did not. Conclusions The HK-DQI is feasible and acceptable to patients. It can be used to assess whether patients with osteoarthritis are making informed decisions about surgery that are concordant with their goals.