Modulating Treg stability to improve cancer immunotherapy.

Immunosuppressive regulatory T cells (Tregs) provide a main mechanism of tumor immune evasion. Targeting Tregs, especially in the tumor microenvironment (TME), continues to be investigated to improve cancer immunotherapy. Recent studies have unveiled intratumoral Treg heterogeneity and plasticity, furthering the complexity of the role of Tregs in tumor immunity and immunotherapy response. The phenotypic and functional diversity of intratumoral Tregs can impact their response to therapy and may offer new targets to modulate specific Treg subsets. In this review we provide a unifying framework of critical factors contributing to Treg heterogeneity and plasticity in the TME, and we discuss how this information can guide the development of more specific Treg-targeting therapies for cancer immunotherapy.

Spectrum of Clinical Presentations, Imaging Findings, and HLA Types in Immune Checkpoint Inhibitor-Induced Hypophysitis.

Context: Hypophysitis is a known immune-related adverse event (irAE) of immune checkpoint inhibitors (CPIs), commonly associated with CTLA-4 inhibitors and less often with PD-1/PD-L1 inhibitors. Objective: We aimed to determine clinical, imaging, and HLA characteristics of CPI-induced hypophysitis (CPI-hypophysitis). Methods: We examined the clinical and biochemical characteristics, magnetic resonance imaging (MRI) of the pituitary, and association with HLA type in patients with CPI-hypophysitis. Results: Forty-nine patients were identified. Mean age was 61.3 years, 61.2% were men, 81.6% were Caucasian, 38.8% had melanoma, and 44.5% received PD-1/PD-L1 inhibitor monotherapy while the remainder received CTLA-4 inhibitor monotherapy or CTLA-4/PD-1 inhibitor combination therapy. A comparison of CTLA-4 inhibitor exposure vs PD-1/PD-L1 inhibitor monotherapy revealed faster time to CPI-hypophysitis (median 84 vs 185 days, P < .01) and abnormal pituitary appearance on MRI (odds ratio 7.00, P = .03). We observed effect modification by sex in the association between CPI type and time to CPI-hypophysitis. In particular, anti-CTLA-4 exposed men had a shorter time to onset than women. MRI changes of the pituitary were most common at the time of hypophysitis diagnosis (55.6% enlarged, 37.0% normal, 7.4% empty or partially empty) but persisted in follow-up (23.8% enlarged, 57.1% normal, 19.1% empty or partially empty). HLA typing was done on 55 subjects; HLA type DQ0602 was over-represented in CPI-hypophysitis relative to the Caucasian American population (39.4% vs 21.5%, P = 0.01) and CPI population. Conclusion: The association of CPI-hypophysitis with HLA DQ0602 suggests a genetic risk for its development. The clinical phenotype of hypophysitis appears heterogenous, with differences in timing of onset, changes in thyroid function tests, MRI changes, and possibly sex related to CPI type. These factors may play an important role in our mechanistic understanding of CPI-hypophysitis.

Predicting and Preventing Immune Checkpoint Inhibitor Toxicity: Targeting Cytokines.

Cancer immunotherapies can successfully activate immune responses towards certain tumors. However, this can also result in the development of treatment-induced immune-related adverse events (irAEs) in multiple tissues. Growing evidence suggests that cytokine production in response to these therapeutics potentiates the development of irAEs and may have predictive value as biomarkers for irAE occurrence. In addition, therapeutic agents that inhibit cytokine activity can limit the severity of irAEs, and their use is being tested in the clinical setting. This review provides an in-depth analysis of strategies to uncouple the cytokine response, that precipitates irAEs following cancer immunotherapies, from the benefit gained in promoting antitumor immunity.

Apical rotation assessed by speckle-tracking echocardiography as an index of global left ventricular contractility.

BACKGROUND: Left ventricular (LV) apical rotation and twist can be estimated noninvasively by speckle-tracking echocardiography (STE). In this study, we tested whether apical rotation is an accurate index of LV contractility. METHODS AND RESULTS: We measured LV basal and apical rotation by STE in 11 open-chest anesthetized mongrel dogs under 8 different inotropic stages before and after ligation of either left anterior descending (n=6) or circumflex coronary artery (n=5). We measured LV pressure simultaneously with a high-fidelity pressure catheter and calculated LV ejection fraction (EF) with the biplane Simpson method and 2D echocardiography. Maximal positive dP/dt (dP/dt(max)) was used as the gold standard measurement of LV contractility. We compared LV twist and apical rotation and EF against dP/dt(max) by linear mixed model. LV apical rotation and twist showed dose-dependent increases and decreases after dobutamine and esmolol infusion, respectively. However, basal rotation did not change significantly during different inotropic conditions. There was a stronger association between dP/dt(max) and LV twist (R(2)=0.747, P<0.001) and apical rotation (R(2)=0.726, P<0.001) than between dP/dt(max) and EF (R(2)=0.408, P<0.001), and this trend was more apparent with coronary ligation irrespective of the ligation site. There was also a high association between dP/dt(max) and apical rotation alone, both with (R(2)=0.805, P<0.001) and without (R(2)=0.748, P<0.001) coronary ligation. Apical rotation alone showed comparable accuracy to LV twist. Apical rotational velocity also showed a high association with dP/dt(max) (R(2)=0.669, P<0.001) and LV twist (R(2)=0.892, P<0.001). CONCLUSIONS: Apical rotation assessed by STE is an effective noninvasive index of global LV contractility and is more closely related to dP/dt(max) than LV EF.