A telomere-targeting drug depletes cancer initiating cells and promotes anti-tumor immunity in small cell lung cancer.

There are few effective treatments for small cell lung cancer (SCLC) underscoring the need for innovative therapeutic approaches. This study focuses on exploiting telomerase, a critical SCLC dependency as a therapeutic target. A prominent characteristic of SCLC is their reliance on telomerase activity, a key enzyme essential for their continuous proliferation. Here we utilize a nucleoside analog, 6-Thio-2'-deoxyguanosine (6TdG) currently in phase II clinical trials, that is preferentially incorporated by telomerase into telomeres leading to telomere dysfunction. Using preclinical mouse and human derived models we find low intermittent doses of 6TdG inhibit tumor growth and reduce metastatic burden. Anti-tumor efficacy correlates with a reduction in a subpopulation of cancer initiating like cells (CICs) identified by their expression of L1CAM/CD133 and highest telomerase activity. 6TdG treatment also leads to activation of innate and adaptive anti-tumor responses. Mechanistically, 6TdG depletes CICs and induces type-I interferon signaling leading to tumor immune visibility by activating tumor cell STING signaling. We also observe increased sensitivity to irradiation after 6TdG treatment in both syngeneic and humanized SCLC xenograft models both of which are dependent on the presence of host immune cells. This study underscores the immune-enhancing and metastasis-reducing effects of 6TdG, employing a range of complementary in vitro and in vivo SCLC preclinical models providing a potential therapeutic approach to SCLC.

Loss of p53 and mutational heterogeneity drives immune resistance in an autochthonous mouse lung cancer model with high tumor mutational burden.

The role of tumor mutational burden (TMB) in shaping tumor immunity is a key question that has not been addressable using genetically engineered mouse models (GEMMs) of lung cancer. To induce TMB in lung GEMMs, we expressed an ultra-mutator variant of DNA polymerase-E (POLE)P286R in lung epithelial cells. Introduction of PoleP286R allele into KrasG12D and KrasG12D; p53L/L (KP) models significantly increase their TMB. Immunogenicity and sensitivity to immune checkpoint blockade (ICB) induced by Pole is partially dependent on p53. Corroborating these observations, survival of NSCLC patients whose tumors have TP53truncating mutations is shorter than those with TP53WT with immunotherapy. Immune resistance is in part through reduced antigen presentation and in part due to mutational heterogeneity. Total STING protein levels are elevated in Pole mutated KP tumors creating a vulnerability. A stable polyvalent STING agonist or p53 induction increases sensitivity to immunotherapy offering therapeutic options in these polyclonal tumors.

Pembrolizumab-Induced Myasthenia Gravis: A Case Report and Review of the Literature.

Myasthenia gravis (MG) is one of the most common neuromuscular adverse effects of immune checkpoint inhibitors (ICIs) and can result in significant morbidity and mortality when it affects the bulbar and respiratory muscles. Diagnosing immune-related MG (irMG) is challenging due to its nonspecific presentation and high negativity rate for MG antibody markers. Patients, primary care providers, and emergency care providers should be educated about MG as a potential adverse effect of ICIs for timely diagnosis and intervention.

Recycling of NdFeB magnets employing oxidation, selective leaching, and iron precipitation in an autoclave.

The increasing production of neodymium-iron-boron (NdFeB) magnets for technological applications results in disposal problems. NdFeB magnets contain a significant quantity of rare earth elements (REEs). China is the largest REEs producer, but it applies quotas and increases the export prices of REEs. To address this issue, this study aims at investigating the recovery process of REEs from scrap NdFeB magnets. After oxidation of NdFeB magnet powders, selective leaching with nitric acid was carried out to achieve high-purity REE-rich leaching liquor. First, the oxidation kinetics of NdFeB powders was studied in detail to determine the oxidation temperature and duration. Afterwards, the effects of selective leaching parameters, including acid concentration, leaching temperature, stirring speed and solid/liquid ratio, were examined by analysis of variance (ANOVA) analysis based on Taguchi method. The most substantial parameters were assigned to be the temperature and solid/liquid ratio. Eventually, the dissolution kinetics were studied to propose a model for REEs. Several universal equations for dissolution kinetics were tested, and (1 - (1 - x) = k × tn) gives the best results for REEs. The findings show that the leaching process follows the shrinking core model. Activation energy was calculated to be 40.375 kJ mol-1 for REEs. As the last step, the iron dissolved during leaching was precipitated as hematite in the autoclave. The hematite precipitation experiments were performed based on the Box-Behnken design. The effect of precipitation parameters was investigated by ANOVA analysis, and the precipitation process was optimized using response surface methodology (RSM), which resulted in the minimum iron and maximum REEs content in the leach liquor.

Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis.

Small cell lung cancer (SCLC) is a pulmonary neuroendocrine cancer with very poor prognosis and limited effective therapeutic options. Most patients are diagnosed at advanced stages, and the exact reason for the aggressive and metastatic phenotype of SCLC is completely unknown. Despite a high tumor mutational burden, responses to immune checkpoint blockade are minimal in patients with SCLC. This may reflect defects in immune surveillance. Here we illustrate that evading natural killer (NK) surveillance contributes to SCLC aggressiveness and metastasis, primarily through loss of NK-cell recognition of these tumors by reduction of NK-activating ligands (NKG2DL). SCLC primary tumors expressed very low level of NKG2DL mRNA and SCLC lines express little to no surface NKG2DL at the protein level. Chromatin immunoprecipitation sequencing showed NKG2DL loci in SCLC are inaccessible compared with NSCLC, with few H3K27Ac signals. Restoring NKG2DL in preclinical models suppressed tumor growth and metastasis in an NK cell-dependent manner. Likewise, histone deacetylase inhibitor treatment induced NKG2DL expression and led to tumor suppression by inducing infiltration and activation of NK and T cells. Among all the common tumor types, SCLC and neuroblastoma were the lowest NKG2DL-expressing tumors, highlighting a lineage dependency of this phenotype. In conclusion, these data show that epigenetic silencing of NKG2DL results in a lack of stimulatory signals to engage and activate NK cells, highlighting the underlying immune avoidance of SCLC and neuroblastoma. SIGNIFICANCE: This study discovers in SCLC and neuroblastoma impairment of an inherent mechanism of recognition of tumor cells by innate immunity and proposes that this mechanism can be reactivated to promote immune surveillance.