Search

Pancreatic neuroendocrine tumors (PNETs) are malignancies arising from the islets of Langerhans. Therapeutic options are limited for the over 50% of patients who present with metastatic disease. We aimed to identify mechanisms to remodel the PNET tumor microenvironment (TME) to ultimately enhance susceptibility to immunotherapy. The TMEs of localized and metastatic PNETs were investigated using an approach that combines RNA-Seq, cancer and T cell profiling, and pharmacologic perturbations. RNA-Seq analysis indicated that the primary tumors of metastatic PNETs showed significant activation of inflammatory and immune-related pathways. We determined that metastatic PNETs featured increased numbers of tumor-infiltrating T cells compared with localized tumors. T cells isolated from both localized and metastatic PNETs showed evidence of recruitment and antigen-dependent activation, suggestive of an immune-permissive microenvironment. A computational analysis suggested that vorinostat, a histone deacetylase inhibitor, may perturb the transcriptomic signature of metastatic PNETs. Treatment of PNET cell lines with vorinostat increased chemokine CCR5 expression by NF-κB activation. Vorinostat treatment of patient-derived metastatic PNET tissues augmented recruitment of autologous T cells, and this augmentation was substantiated in a mouse model of PNET. Pharmacologic induction of chemokine expression may represent a promising approach for enhancing the immunogenicity of metastatic PNET TMEs.

Vemurafenib, an inhibitor of mutant BRAF activity, is a promising anticancer agent for patients with BRAF-mutant metastatic melanoma. However, it is less effective in BRAF-mutant thyroid cancer, and the reason for this discrepancy is not yet fully elucidated. By RNA sequencing analysis, we identified vascular cell adhesion molecular-1 (VCAM-1) to be highly upregulated in both time- and dose-dependent manners during BRAF inhibition (BRAFi) in a BRAF-mutant papillary thyroid cancer cell line (BCPAP). Cell cytotoxicity and apoptosis assays showed that knockdown of the induced VCAM-1 in BCPAP cells augmented the antitumor effects of vemurafenib, with decreased IC50 values of 1.4 to 0.8 μM. Meanwhile, overexpression of VCAM-1 in a BRAF-mutant anaplastic thyroid cancer cell line (FRO) reduced the sensitivity to vemurafenib, with increased IC50 values of 1.9 to 5.8 μM. Further investigation showed that PI3K-Akt-mTOR pathway was activated during BRAFi. Co-treatment with Akt signaling inhibitor MK2206 decreased the induced expression of VCAM-1 during BRAFi. This combination further improved the efficacy of vemurafenib. Moreover, VCAM-1 promoted migration and invasion in thyroid cancer cells in vitro, which was also indicated in thyroid cancer patients. The present study is the first to demonstrate that VCAM-1 is upregulated in thyroid cancer cells treated with vemurafenib and contributes to vemurafenib resistance in BRAF-mutant thyroid cancer cells. Targeting the PI3K-Akt-mTOR pathway–mediated VCAM-1 response may be an alternative strategy to sensitize BRAF-mutant thyroid cancers to vemurafenib.

Hypertension causes significant morbidity and mortality worldwide, owing to its deleterious effects on the cardiovascular and renal systems. Primary hyperaldosteronism (PA) is the most common cause of reversible hypertension, affecting 5%-18% of adults with hypertension. PA is estimated to result from bilateral adrenal hyperplasia in two-thirds of patients, and from unilateral aldosterone-secreting adenoma in approximately one-third. Suspected cases are initially screened by measurement of the plasma aldosterone-renin-ratio, and may be confirmed by additional noninvasive tests. Localization of aldostosterone hypersecretion is then determined by computed tomography imaging, and in selective cases with adrenal vein sampling. Solitary adenomas are managed by laparoscopic or robotic resection, while bilateral hyperplasia is treated with mineralocorticoid antagonists. Biochemical cure following adrenalectomy occurs in 99% of patients, and hemodynamic improvement is seen in over 90%, prompting a reduction in quantity of anti-hypertensive medications in most patients. End-organ damage secondary to hypertension and excess aldosterone is significantly improved by both surgical and medical treatment, as manifested by decreased left ventricular hypertrophy, arterial stiffness, and proteinuria, highlighting the importance of proper diagnosis and treatment of primary hyperaldosteronism. Although numerous independent predictors of resolution of hypertension after adrenalectomy for unilateral adenomas have been described, the Aldosteronoma Resolution Score is a validated multifactorial model convenient for use in daily clinical practice.