Targeting T cell immunometabolism for cancer immunotherapy; understanding the impact of the tumor microenvironment.

The immune system has a key role to play in controlling cancer initiation and progression. T cell activation, which is central to anti-tumor immune responses, coincides with changes in cellular metabolism. Naïve T cells predominantly require an ATP generating metabolic profile, whereas proliferating effector T cells require anabolic metabolic profiles that promote rapid growth and proliferation. Furthermore, specific T cell subsets require distinct energetic and biosynthetic pathways to match their functional requirements. The often hostile tumor microenvironment can affect T cell immune responses by altering the resulting cellular metabolism. Tailoring immune responses by manipulating cellular metabolic pathways may provide an exciting new option for cancer immunotherapy. T cell responses might also be skewed via metabolic manipulation to treat the complications of obesity-associated inflammation, which is a rapidly growing global health problem and a major risk factor for many malignancies. In this review, the diverse metabolic requirements of T cells in anti-tumor immunity are discussed, as well as the profound influence of the tumor microenvironment and the possible avenues for manipulation to enhance anti-tumor immunity.

Causes and consequences of nonpersistence with heart failure medication.

Persistence with therapy may be more easily and objectively identified in the clinical setting than compliance and recent work has shown it to be linked to mortality in heart failure (HF). The aim of this study was to determine the extent, causes, and clinical impact of nonpersistence with disease-modifying therapy in a retrospective cohort study of 183 patients with systolic HF participating in a disease management program. The main outcome measurements were reasons/determinants of nonpersistence and its impact on hospitalizations. Fifty-three patients (29%) had 74 separate occurrences of nonpersistence with disease-modifying therapy. There was no medical reason for discontinuing medications in 50% of occurrences, whereas medication was discontinued for an adverse reaction in 30% and for a justified medical reason in 15% of occurrences. Nonpersistence was a significant predictor of all-cause readmission (hazard ratio 3.20, 95% confidence interval 1.74 to 11.37) and cardiovascular readmission (hazard ratio 4.45, 95% confidence interval 1.74 to 11.37). In the adjusted model, there was no significantly increased risk of HF readmission (hazard ratio 2.41, 95% confidence interval 0.88 to 6.62). In conclusion, nonpersistence with HF therapy is common, is often not medically justified, and is associated with an increased risk of hospitalization.