Immunotherapy holds tremendous promise for improving cancer treatment1. Administering radiotherapy with immunotherapy has been shown to improve immune responses and can elicit an “abscopal effect”2. Unfortunately, response rates for this strategy remain low3. Herein, we report an improved cancer immunotherapy approach that utilizes antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NPs formulations and demonstrated that the set of protein antigens captured by each AC-NP formulation is dependent upon NP surface properties. We showed that AC-NPs deliver tumor specific proteins to antigen-presenting cells and significantly improve the efficacy of αPD-1 treatment using the B16F10 melanoma model, generating up to 20% cure rate as compared to 0% without AC-NPs. Mechanistic studies revealed that AC-NPs induced an expansion of CD8+ cytotoxic T cells and increased both CD4+/Treg and CD8+/Treg ratios. Our work presents a novel strategy for improving cancer immunotherapy with nanotechnology.
ONC201
is a first-in-class imipridone molecule currently in clinical
trials for the treatment of multiple cancers. Despite enormous clinical
potential, the mechanism of action is controversial. To investigate
the mechanism of ONC201 and identify compounds with improved potency,
we tested a series of novel ONC201 analogues (TR compounds) for effects
on cell viability and stress responses in breast and other cancer
models. The TR compounds were found to be ∼50–100 times
more potent at inhibiting cell proliferation and inducing the integrated
stress response protein ATF4 than ONC201. Using immobilized TR compounds,
we identified the human mitochondrial caseinolytic protease P (ClpP)
as a specific binding protein by mass spectrometry. Affinity chromatography/drug
competition assays showed that the TR compounds bound ClpP with ∼10-fold
higher affinity compared to ONC201. Importantly, we found that the
peptidase activity of recombinant ClpP was strongly activated by ONC201
and the TR compounds in a dose- and time-dependent manner with the
TR compounds displaying a ∼10–100 fold increase in potency
over ONC201. Finally, siRNA knockdown of ClpP in SUM159 cells reduced
the response to ONC201 and the TR compounds, including induction of
CHOP, loss of the mitochondrial proteins (TFAM, TUFM), and the cytostatic
effects of these compounds. Thus, we report that ClpP directly binds
ONC201 and the related TR compounds and is an important biological
target for this class of molecules. Moreover, these studies provide,
for the first time, a biochemical basis for the difference in efficacy
between ONC201 and the TR compounds.
We conclude that chronic vaping exerts marked biological effects on the lung and that these effects may in part be mediated by the PG/VG base. These changes are likely not harmless and may have clinical implications for the development of chronic lung disease. Further studies will be required to determine the full extent of vaping on the lung.
SUMMARY
Our recent ERK1/2 inhibitor analyses in pancreatic ductal adenocarcinoma (PDAC) indicated ERK1/2-independent mechanisms maintaining MYC protein stability. To identify these mechanisms, we determined the signaling networks by which mutant KRAS regulates MYC. Acute KRAS suppression caused rapid proteasome-dependent loss of MYC protein, through both ERK1/2-dependent and -independent mechanisms. Surprisingly, MYC degradation was independent of PI3K-AKT-GSK3β signaling and the E3 ligase FBWX7. We then established and applied a high-throughput screen for MYC protein degradation and performed a kinome-wide proteomics screen. We identified an ERK1/2-inhibition-induced feed-forward mechanism dependent on EGFR and SRC, leading to ERK5 activation and phosphorylation of MYC at S62, preventing degradation. Concurrent inhibition of ERK1/2 and ERK5 disrupted this mechanism, synergistically causing loss of MYC and suppressing PDAC growth.
SUMMARY
Increased glucose metabolism in immune cells not only serves as a hallmark feature of acute inflammation, but also profoundly affects disease outcome following bacterial infection and tissue damage. However, the role of individual glucose metabolic pathways during viral infection remains largely unknown. Here we demonstrate an essential function of the hexosamine biosynthesis pathway (HBP)-associated O-linked β-N-acetylglucosamine (O-GlcNAc) signaling in promoting antiviral innate immunity. Challenge of macrophages with vesicular stomatitis viruses (VSV) enhances HBP activity and downstream protein O-GlcNAcylation. Human and murine cells deficient of O-GlcNAc transferase, a key enzyme for protein O-GlcNAcylation, show defective antiviral immune responses upon VSV challenge. Mechanistically, OGT-mediated O-GlcNAcylation of the signaling adaptor MAVS on serine 366 (S366) is required for K63-linked ubiquitination of MAVS and subsequent downstream RLR-antiviral signaling activation. Thus, our study identifies a molecular mechanism by which HBP-mediated O-GlcNAcylation regulates MAVS function and highlights the importance of glucose metabolism on antiviral innate immunity.
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