Activation of endogenous glucocorticoids by HSD11B1 inhibits the antitumor immune response in renal cancer.

Although immune-based therapies have revolutionized the management of cancer, novel approaches are urgently needed to improve their outcome. We investigated the role of endogenous steroids in the resistance to cancer immunotherapy, as these have strong immunomodulatory functions. Using a publicly available database, we found that the intratumoral expression of 11 beta-hydroxysteroid dehydrogenase type 1 (HSD11B1), which regenerates inactive glucocorticoids into active glucocorticoids, was associated with poor clinical outcome and correlated with immunosuppressive gene signatures in patients with renal cell carcinoma (RCC). HSD11B1 was mainly expressed in tumor-infiltrating immune myeloid cells as seen by immunohistochemistry in RCC patient samples. Using peripheral blood mononuclear cells from healthy donors or immune cells isolated from the tumor of RCC patients, we showed that the pharmacological inhibition of HSD11B1 improved the response to the immune checkpoint inhibitor anti-PD-1. In a subcutaneous mouse model of renal cancer, the combination of an HSD11B1 inhibitor with anti-PD-1 treatment increased the proportion of tumor-infiltrating dendritic cells. In an intrarenal mouse tumor model, HSD11B1 inhibition increased the survival of mice treated with anti-PD-1. In addition, inhibition of HSD11B1 sensitized renal tumors in mice to immunotherapy with resiquimod, a Toll-like receptor 7 agonist. Mechanistically, we demonstrated that HSD11B1 inhibition combined with resiquimod increased T cell-mediated cytotoxicity to tumor cells by stimulating the antigen-presenting capacity of dendritic cells. In conclusion, these results support the use of HSD11B1 inhibitors to improve the outcome of immunotherapy in renal cancer and highlight the role of the endogenous glucocorticoid metabolism in the efficacy of immunotherapy.

Activation of the Hypoxia-Inducible Factor Pathway Inhibits Epithelial Sodium Channel-Mediated Sodium Transport in Collecting Duct Principal Cells.

BACKGROUND: Active sodium reabsorption is the major factor influencing renal oxygen consumption and production of reactive oxygen species (ROS). Increased sodium reabsorption uses more oxygen, which may worsen medullary hypoxia and produce more ROS via enhanced mitochondrial ATP synthesis. Both mechanisms may activate the hypoxia-inducible factor (HIF) pathway. Because the collecting duct is exposed to low oxygen pressure and variations of active sodium transport, we assessed whether the HIF pathway controls epithelial sodium channel (ENaC)-dependent sodium transport. METHODS: We investigated HIF's effect on ENaC expression in mpkCCD cl4 cells (a model of collecting duct principal cells) using real-time PCR and western blot and ENaC activity by measuring amiloride-sensitive current. We also assessed the effect of hypoxia and sodium intake on abundance of kidney sodium transporters in wild-type and inducible kidney tubule-specific Hif1α knockout mice. RESULTS: In cultured cells, activation of the HIF pathway by dimethyloxalylglycine or hypoxia inhibited sodium transport and decreased expression of ß ENaC and γ ENaC, as well as of Na,K-ATPase. HIF1 α silencing increased ß ENaC and γ ENaC expression and stimulated sodium transport. A constitutively active mutant of HIF1 α produced the opposite effect. Aldosterone and inhibition of the mitochondrial respiratory chain slowly activated the HIF pathway, suggesting that ROS may also activate HIF. Decreased γ ENaC abundance induced by hypoxia in normal mice was abolished in Hif1α knockout mice. Similarly, Hif1α knockout led to increased γ ENaC abundance under high sodium intake. CONCLUSIONS: This study reveals that γ ENaC expression and activity are physiologically controlled by the HIF pathway, which may represent a negative feedback mechanism to preserve oxygenation and/or prevent excessive ROS generation under increased sodium transport.

Thyroid Rosai-Dorfman disease with infiltration of IgG4-bearing plasma cells associated with multiple small pulmonary cysts.

BACKGROUND: Rosai-Dorfman disease (RDD) is a rare histiocytosis which involves principally lymph nodes. Thyroid involvement in RDD is a very rare situation, and lung involvement is even rarer. CASE PRESENTATION: We report the case of a 46-year-old woman presenting a painless mass in the right side of the neck and subacute dyspnoea. Computerised tomography (CT) scans of the neck and thorax showed a large thyroid mass causing tracheal stenosis and multiple cystic lesions in both lungs. Subtotal thyroidectomy with a tracheal segment resection and histological analysis confirmed the diagnosis of nodal and extranodal (thyroid, tracheal and probably lung) Rosai-Dorfman disease (RDD) with the presence of increased numbers of IgG4-bearing plasma cells. Clinical, functional and radiological follow up 4 years after surgery without medical treatment did not show any disease progression. CONCLUSIONS: This case report indicates a benign course of nodal RDD with thyroid and tracheal infiltration following surgical resection, association of typical histological signs of RDD (emperipolesis) with IgG4-related disease features, and that lung cysts might be a manifestation of RDD.

Biliary Involvement in Type 2 Autoimmune Pancreatitis.

Autoimmune pancreatitis (AIP) is a rare condition classified in 2 subtypes. Their distinction relies on a combination of clinical, serological, morphological and histological features. Type 1 is a pancreatic manifestation of IgG4-related disease characterized by multiorgan infiltration by IgG4 plasmocytes. In this condition, hepatobiliary infiltration is frequent and often mimics cholangiocarcinoma or primary sclerosing cholangitis. On the other hand, type 2 is commonly limited to the pancreas. Herein, we describe the case of a patient who presented a type 2 AIP associated with cholangiopathy, a condition not described in the established criteria. He first developed a pancreatitis identified as type 2 by the typical histopathological features and lack of IgG4 in the serum and tissue. Despite a good clinical response to steroids, cholestasis persisted, identified by MR cholangiography as a stricture of the left hepatic duct with dilatation of the intrahepatic bile duct in segments 2 and 3. Biliary cytology was negative. Evolution was favorable but after steroid tapering a few months later, the patient suffered from recurrence of the pancreatitis as well as progression of biliary attempt, suspicious for cholangiocarcinoma. As the investigations again ruled out neoplastic infiltration or primary sclerosing cholangitis, azathioprine was initiated with resolution of both pancreatic and biliary attempts.

"Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features" With Focal Spindle Cell Metaplasia.

"Noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) is a recent reclassification of the encapsulated follicular variant of papillary thyroid carcinoma, which is supposed to reflect its indolent clinical behavior and to prevent overtreatment of patients with this neoplasm. The diagnosis of NIFTP can only be made histologically on the surgical specimen according to specific inclusion and exclusion criteria, which requires the examination of the whole nodule and its capsule. Spindle cell proliferations, especially of follicular cell origin, arising within thyroid follicular neoplasms are very rare and may cause diagnostic difficulties. Few reports described spindle cell proliferations arising in follicular thyroid adenoma and papillary thyroid carcinoma. To the best of our knowledge, only one case has been reported in NIFTP so far. In this article, we report a unique case of NIFTP associated with a spindle cell proliferation that was characterized immunohistochemically. Specific issues related to this case are discussed.