Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8+ T cell formation.

Mitophagy, a central process guarding mitochondrial quality, is commonly impaired in human diseases such as Parkinson's disease, but its impact in adaptive immunity remains unclear. The differentiation and survival of memory CD8+ T cells rely on oxidative metabolism, a process that requires robust mitochondrial quality control. Here, we found that Parkinson's disease patients have a reduced frequency of CD8+ memory T cells compared with healthy donors and failed to form memory T cells upon vaccination against COVID-19, highlighting the importance of mitochondrial quality control for memory CD8+ T cell formation. We further uncovered that regulators of mitophagy, including Parkin and NIX, were up-regulated in response to interleukin-15 (IL-15) for supporting memory T cell formation. Mechanistically, Parkin suppressed VDAC1-dependent apoptosis in memory T cells. In contrast, NIX expression in T cells counteracted ferroptosis by preventing metabolic dysfunction resulting from impaired mitophagy. Together, our results indicate that the mitophagy machinery orchestrates survival and metabolic dynamics required for memory T cell formation, as well as highlight a deficit in T cell-mediated antiviral responses in Parkinson's disease patients.

Microenvironment-driven metabolic adaptations guiding CD8+ T cell anti-tumor immunity.

The metabolic stress occurring in the tumor microenvironment (TME) hampers T cell anti-tumor immunity by disturbing T cell metabolic and epigenetic programs. Recent studies are making headway toward identifying strategies to unleash T cell activities by targeting T cell metabolism. Furthermore, efforts have been made to improve the efficacy of immune checkpoint blockade and adoptive cell transfer therapies. However, distinct treatment outcomes across different cancers raise the question of whether our understanding of the features of CD8+ T cells within the TME are universal, regardless of their tissue of origin. Here, we review the common and distinct environmental factors affecting CD8+ T cells across tumors. Moreover, we discuss how distinct tissue-specific niches are interpreted by CD8+ T cells based on studies on tissue-resident memory T (Trm) cells and how these insights can pave the way for a better understanding of the metabolic regulation of CD8+ T cell differentiation and anti-tumor immunity.

Metabolic guidance and stress in tumors modulate antigen-presenting cells.

Successful antitumor immunity largely relies on efficient T cell priming by antigen-presenting cells (APCs); however, the capacity of APCs is found to be defective in many cancers. Metabolically reprogrammed cancer cells support the energetic and biosynthetic demands of their high proliferation rates by exploiting nutrients available in the tumor microenvironment (TME), which in turn limits proper metabolic reprogramming of APCs during recruitment, differentiation, activation and antigen presentation. Furthermore, some metabolites generated by the TME are unfavorable to antitumor immunity. This review summarizes recent studies on the metabolic features of APCs and their functionality in the TME. Particularly, we will describe how APCs respond to altered TME and how metabolic byproducts from cancer and immunomodulatory cells affect APCs. Finally, we introduce the current status of APC-oriented research and clinical trials targeting metabolic features to boost efficient immunotherapy.

YAP and AP-1 Cooperate to Initiate Pancreatic Cancer Development from Ductal Cells in Mice.

The development of pancreatic cancer is heavily dependent upon the aberrant activation of KRAS signaling. Among the downstream targets of KRAS, the effectors of the Hippo pathway YAP and TAZ (YAP/TAZ) are crucial during cancer initiation and progression. However, little is known about the cell type-specific effects of YAP/TAZ on the development of pancreatic cancer. Here we clarify the unique consequences of YAP/TAZ activation in the ductal cell population of the pancreas by generating mice with pancreatic duct cell-specific, inducible knockouts of Lats1 and Lats2, the main kinases upstream of YAP/TAZ. Oncogenic activation of YAP by deletion of Lats1/2 in ductal cells led to the rapid transformation of the pancreas, which was accompanied by a robust increase in the expression of YAP and AP-1 target genes. Pharmacologic inhibition of AP-1 activity induced death in Lats1/2 knockout organoids and attenuated YAP-dependent transformation of the pancreas in vivo. Both YAP and AP-1 were activated during the development of KRAS-dependent cancer in mice and human patients with pancreatic ductal adenocarcinoma, suggesting that this signaling hub represents an important mediator of pancreatic cancer development and progression. Collectively, these data define a YAP-dependent mechanism of pancreatic cancer cell development and suggest that inhibition of AP-1 can suppress this development. SIGNIFICANCE: A pancreatic ductal cell-specific knockout mouse model featuring constitutively active YAP allows for the study of YAP-dependent transformation of the pancreas and for screening pharmacologically active inhibitors.

WWC1 and NF2 Prevent the Development of Intrahepatic Cholangiocarcinoma by Regulating YAP/TAZ Activity through LATS in Mice.

Hippo signaling acts as a tumor suppressor pathway by inhibiting the proliferation of adult stem cells and progenitor cells in various organs. Liver-specific deletion of Hippo pathway components in mice induces liver cancer development through activation of the transcriptional coactivators, YAP and TAZ, which exhibit nuclear enrichment and are activated in numerous types of cancer. The upstream-most regulators of Warts, the Drosophila ortholog of mammalian LATS1/2, are Kibra, Expanded, and Merlin. However, the roles of the corresponding mammalian orthologs, WWC1, FRMD6 and NF2, in the regulation of LATS1/2 activity and liver tumorigenesis in vivo are not fully understood. Here, we show that deletion of both Wwc1 and Nf2 in the liver accelerates intrahepatic cholangiocarcinoma (iCCA) development through activation of YAP/TAZ. Additionally, biliary epithelial cell-specific deletion of both Lats1 and Lats2 using a Sox9-CreERT2 system resulted in iCCA development through hyperactivation of YAP/TAZ. These findings suggest that WWC1 and NF2 cooperate to promote suppression of cholangiocarcinoma development by inhibiting the oncogenic activity of YAP/TAZ via LATS1/2.

YAP/TAZ Initiates Gastric Tumorigenesis via Upregulation of MYC.

YAP and TAZ play oncogenic roles in various organs, but the role of YAP/TAZ in gastric cancer remains unclear. Here, we show that YAP/TAZ activation initiates gastric tumorigenesis in vivo and verify its significance in human gastric cancer. In mice, YAP/TAZ activation in the pyloric stem cell led to step-wise tumorigenesis. RNA sequencing identified MYC as a decisive target of YAP, which controls MYC at transcriptional and posttranscriptional levels. These mechanisms tightly regulated MYC in homeostatic conditions, but YAP activation altered this balance by impeding miRNA processing, causing a shift towards MYC upregulation. Pharmacologic inhibition of MYC suppressed YAP-dependent phenotypes in vitro and in vivo, verifying its functional role as a key mediator. Human gastric cancer samples also displayed a significant correlation between YAP and MYC. We reanalyzed human transcriptome data to verify enrichment of YAP signatures in a subpopulation of gastric cancers and found that our model closely reflected the molecular pattern of patients with high YAP activity. Overall, these results provide genetic evidence of YAP/TAZ as oncogenic initiators and drivers for gastric tumors with MYC as the key downstream mediator. These findings are also evident in human gastric cancer, emphasizing the significance of YAP/TAZ signaling in gastric carcinogenesis.Significance: YAP/TAZ activation initiates gastric carcinogenesis with MYC as the key downstream mediator. Cancer Res; 78(12); 3306-20. ©2018 AACR.

Estimation of Lead Exposure Prevalence in Korean Population through Combining Multiple Experts' Judgment based on Objective Data Sources.

Objective: Estimating carcinogen exposure prevalence is important for preventing occupational cancers. To develop the Korean version of CARcinogen EXposure (CAREX), a carcinogen surveillance system used in many countries, we estimated lead exposure prevalence in the Korean working population. Methods: We used three Korean nationwide data sources to obtain objective database-derived prevalences of lead exposure across industries: airborne lead measurement data from the work environment measurement database (WEMD), blood lead measurement data from the special health examination database (SHED), and lead exposure prevalence computed using data from the work environment condition survey (WECS), which is a nationwide occupational exposure survey. We also asked a panel of 52 experts with ≥20 years of experience in industrial hygiene practice for their judgment about lead exposure prevalence across industries after they reviewed the database-derived prevalences computed from the three exposure databases. We developed and compared various estimation methods for combining the experts' judgments. The 2010 census was used as the reference population to estimate the number of lead-exposed workers in 228 industries by multiplying the exposure prevalence by the number of workers in each industry. Results: The database-derived prevalences of lead exposure in the 228 industries were calculated using data collected between 2009 and 2011 from the WEMD and SHED and from the 2009 WECS. From the various estimation methods assessed, the median values of experts' responses were selected as our estimates of lead exposure prevalence in each industry. As a result, it was estimated that 129,250 Korean workers were exposed to lead in 2010. Conclusions: Based on objective databases, we developed a method for estimating exposure prevalence for the CAREX system by combining experts' judgments. This work may offer an unbiased approach to the development process that accounts for the uncertainty in exposure.

The Effects of an Online Mind-Body Training Program on Stress, Coping Strategies, Emotional Intelligence, Resilience and Psychological State.

The goal of this study was to evaluate the effects of an online mind-body training (MBT) program on participants' stress, anger, coping strategies, emotional intelligence, resilience, and positive and negative affect. Forty-two healthy women participated in an online MBT program for approximately 8-10 minutes a day for 8 weeks; a control group of 45 healthy women did not participate in the program. Self-report psychological questionnaires were administered before the beginning of the program and at 4 and 8 weeks following its onset. Data from the MBT group and the control group were compared using repeated measures ANOVA and Student's t-tests. Significant time x group interaction effects were found with respect to stress, coping strategies, anger, emotional intelligence, negative affect and resilience. These results demonstrate beneficial effects of the online MBT program and significant improvements in the psychological capabilities of participants compared with the control group. The effects of online MBT program were similar with those of the previous offline MBT in psychological aspects, suggesting further studies for neuroscientific evidence related stress and emotion of online MBT effects.

Case report of renal cell carcinoma in automobile manufacturing factory worker due to trichloroethylene exposure in Korea.

BACKGROUND: The aim of this paper was report first case of renal cell carcinoma developed in a worker who worked in an automobile manufacture line which handles trichloroethylene in Korea. CASE PRESENTATION: To clarify the relationship between the onset of renal cell carcinoma in 52-years old male worker and the exposure to trichloroethylene, document studies and work environment measurement were done. Past work environment exposure data were reviewed and medical history and surgery records of the worker were also reviewed. The patient had no personal risk factor related to renal cell carcinoma except for his smoking habit of quarter a pack per day for twenty years, and since trichloroethylene was not part of measurement criteria, past work environment risk assessment data could not verify the exposure. The exposure level is deduced by analyzing material exposure level of work environments which has similar processes in data from revised research of chemical exposure standard and work environment validity assessment. Evaluation Committee of Epidemiologic Survey decided that there are relevant relationship between the exposure and the disease, though we do not have exact data during that period, most experts agree that in every factories they used trichloroethylene without any direction. CONCLUSIONS: From the relevant medical history and the results of the usage of trichloroethylene in the relevant industries, and initial discovery of renal cell carcinoma at health inspection sonogram in 2001, it can be concluded that suggests significant causal relationship between the exposure to trichloroethylene and renal cell carcinoma onset, thus reporting it to be the first domestic case declared to be occupational disease.