ABSTRACT
Cell proteostasis includes gene transcription, protein translation, folding of de novo proteins, post-translational modifications, secretion, degradation and recycling. By profiling the proteome of extracellular vesicles (EVs) from T cells, we have found the chaperonin complex CCT, involved in the correct folding of particular proteins. By limiting CCT cell-content by siRNA, cells undergo altered lipid composition and metabolic rewiring towards a lipid-dependent metabolism, with increased activity of peroxisomes and mitochondria. This is due to dysregulation of the dynamics of interorganelle contacts between lipid droplets, mitochondria, peroxisomes and the endolysosomal system. This process accelerates the biogenesis of multivesicular bodies leading to higher EV production through the dynamic regulation of microtubule-based kinesin motors. These findings connect proteostasis with lipid metabolism through an unexpected role of CCT.
Subject(s)
Extracellular Vesicles , Kinesins , Kinesins/metabolism , Chaperonin Containing TCP-1/metabolism , Extracellular Vesicles/metabolism , Lipid Metabolism , LipidsABSTRACT
BACKGROUND: Lung cancer is one of the most frequent malignancies in humans and is a major cause of death. A number of therapies aimed at reinforcing antitumor immune response, including antiprogrammed cell death protein 1 (anti-PD-1) antibodies, are successfully used to treat several neoplasias as non-small cell lung cancer (NSCLC). However, host immune mechanisms that participate in response to anti-PD-1 therapy are not completely understood. METHODS: We used a syngeneic immunocompetent mouse model of NSCLC to analyze host immune response to anti-PD-1 treatment in secondary lymphoid organs, peripheral blood and tumors, by flow cytometry, immunohistochemistry and quantitative real-time PCR (qRT-PCR). In addition, we also studied specific characteristics of selected immune subpopulations in ex vivo functional assays. RESULTS: We show that anti-PD-1 therapy induces a population of circulating T follicular helper cells (cTfh) with enhanced B activation capacity, which participates in tumor response to treatment. Anti-PD-1 increases the number of tertiary lymphoid structures (TLS), which correlates with impaired tumor growth. Of note, TLS support cTfh-associated local antibody production, which participates in host immune response against tumor. CONCLUSION: These findings unveil a novel mechanism of action for anti-PD-1 therapy and provide new targets for optimization of current therapies against lung cancer.
Subject(s)
Immune Checkpoint Inhibitors/therapeutic use , T Follicular Helper Cells/drug effects , Animals , Disease Models, Animal , Humans , Immune Checkpoint Inhibitors/pharmacology , Male , MiceABSTRACT
OBJECTIVE: To characterize the temporal and spatial distribution and reproductive ratio of vesicular stomatitis (VS) outbreaks reported in Mexico in 2008. ANIMALS: Bovine herds in Mexico in which VS outbreaks were officially reported and confirmed from January 1 through December 31, 2008. PROCEDURES: The Poisson model of the space-time scan statistic was used to identify periods and geographical locations at highest risk for VS in Mexico in 2008. The herd reproductive ratio (R(h)) of the epidemic was computed by use of the doubling-time method. RESULTS: 1 significant space-time cluster of VS was detected in the state of Michoacan from September 4 through December 10, 2008. The temporal extent of the VS outbreaks and the value and pattern of decrease of the R(h) were different in the endemic zone of Tabasco and Chiapas, compared with findings in the region included in the space-time cluster. CONCLUSIONS AND CLINICAL RELEVANCE: The large number of VS outbreaks reported in Mexico in 2008 was associated with the spread of the disease from the endemic zone in southern Mexico to areas sporadically affected by the disease. Results suggested that implementation of a surveillance system in the endemic zone of Mexico aimed at early detection of changes in the value of R(h) and space-time clustering of the disease could help predict occurrence of future VS outbreaks originating from this endemic zone. This information will help prevent VS spread into regions of Mexico and neighboring countries that are only sporadically affected by the disease.
