No abstract

Alterations in SMARCA4, a member of the chromatin remodeling Switch Sucrose Non-Fermentable (SWI/SNF) complex, characterize a subset of non-small cell lung cancer (NSCLC), but detailed morphological and immunophenotypic description of this tumor type is lacking. We describe 20 NSCLC cases found on routine screening not to express SMARCA4 by immunohistochemistry (IHC). These tumors were stained for CK7, TTF1, SMARCA2, SMARCA4, SMARCB1, and HepPar-1 and analyzed for molecular alterations, using a 160 cancer-related gene panel including the full coding sequence of SMARCA4. Patients were eight females and 12 males aged 41 to 76 (median, 60). Of 18 tumors with detailed data, 14 presented with synchronous distant metastases (M1). Histological examination showed predominantly solid adenocarcinoma (n = 15), frankly rhabdoid (n = 3) and mucinous (n = 2) patterns. Except for the rhabdoid cases, all tumors showed at least focal unequivocal glands and lacked squamous differentiation, justifying a diagnosis of adenocarcinoma. IHC showed a distinctive uniform immunophenotype (CK7/HepPar-1/TTF1) in 18/20 cases. Only 2/16 cases showed limited weak expression of neuroendocrine markers. EGFR mutations and EML4-ALK and ROS1 gene rearrangements were not found in any of the examined cases. Next-generation sequencing, using a 160 cancer-related gene panel, revealed concurrent SMARCA4 and TP53 mutations in nine of the 12 (75%) successfully tested cases. Our study highlights (1) the morphological diversity of SMARCA4-deficient lung adenocarcinoma, (2) the consistent absence of expression of TTF1 in the presence of expression of HepPar-1, (3) absence of EGFR driver mutations, and (4) frequent inactivating SMARCA4 mutations as underlying mechanism of the observed SMARCA4 protein loss. SMARCA4-deficient pulmonary adenocarcinoma is emerging as a distinctive, albeit phenotypically heterogeneous molecular subgroup of TTF1-negative NSCLC. Uniform HepPar-1 expression in this subset of NSCLC may represent a diagnostic pitfall and merits further studies to explore the mechanisms involved.

Despite recent advances in activating immune cells to target tumors, the presence of some immune cells, such as tumor-associated macrophages (TAMs) or tumor-associated neutrophils (TANs), may promote rather than inhibit tumor growth. However, it remains unclear how antibody-dependent tumor immunotherapies, such as cytotoxic or checkpoint control antibodies, affect different TAM or TAN populations, which abundantly express activating Fcγ receptors. In this study, we show that the tissue environment determines which cellular effector pathways are responsible for antibody-dependent tumor immunotherapy. Although TAMs derived from Ly6C monocytes recruited by the CCL2-CCR2 axis were critical for tumor immunotherapy of skin tumors, the destruction of lung tumors was CCL2-independent and required the presence of colony-stimulating factor 2-dependent tissue-resident macrophages. Our findings suggest that TAMs may have a dual role not only in promoting tumor growth in certain tissue environments on the one hand but also in contributing to tumor cell destruction during antibody-mediated immunotherapy on the other hand.

Background:Lung cancer is the most life-threatening cancer type worldwide. Treatment options include surgery, radio- and chemotherapy, as well as the use of immunomodulatory antibodies. Interleukin (IL)-10 is an immunosuppressive cytokine involved in tumour immune escape.Methods:Immunohistochemistry (IHC) on human lung surgery tissue as well as human tumour cell line cultures, FACS analysis, real-time PCR and experimental lung cancer.Results:Here we discovered a positive correlation between IL-10 and IL-10 receptor (IL-10R) expression in the lung with tumour diameter in patients with lung cancer (non-small cell lung cancer), the most life-threatening cancer type worldwide. IL-10 and IL-10R were found induced in cells surrounding the lung tumour cells, and IL-10R was mainly expressed on the surface of Foxp-3+ T-regulatory lymphocytes infiltrating the tumour of these patients where its expression inversely correlated with programmed cell death 1. These findings were confirmed in translational studies. In a human lung adenocarcinoma cell line, IL-10R was found induced under metabolic restrictions present during tumour growth, whereby IL-10 inhibited PDL1 and tumour cell apoptosis.Conclusions:These new findings suggest that IL-10 counteracts IFN-γ effects on PD1/PDL1 pathway, resulting in possible resistance of the tumour to anti-PD1/PDL1 immunotherapy.

Aims The aim of this official guideline published and coordinated by the German Society of Gynaecology and Obstetrics (DGGG) in cooperation with the Austrian Society for Gynaecology and Obstetrics (OEGGG) and the Swiss Society for Gynaecology and Obstetrics (SGGG) was to provide consensus-based recommendations for the diagnosis and treatment of endometriosis based on an evaluation of the relevant literature. Methods This S2k guideline represents the structured consensus of a representative panel of experts with different professional backgrounds commissioned by the Guideline Committee of the DGGG, OEGGG and SGGG. Recommendations Recommendations on the epidemiology, aetiology, classification, symptomatology, diagnosis and treatment of endometriosis are given and special situations are discussed.