Melissa Johnson

The metabolic landscape of cancer greatly influences antitumor immunity, yet it remains unclear how organ-specific metabolites in the tumor microenvironment influence immunosurveillance. We found that accumulation of primary conjugated and secondary bile acids (BAs) are metabolic features of human hepatocellular carcinoma and experimental liver cancer models. Inhibiting conjugated BA synthesis in hepatocytes through deletion of the BA-conjugating enzyme bile acid–CoA:amino acid N -acyltransferase (BAAT) enhanced tumor-specific T cell responses, reduced tumor growth, and sensitized tumors to anti–programmed cell death protein 1 (anti–PD-1) immunotherapy. Furthermore, different BAs regulated CD8 + T cells differently; primary BAs induced oxidative stress, whereas the secondary BA lithocholic acid inhibited T cell function through endoplasmic reticulum stress, which was countered by ursodeoxycholic acid. We demonstrate that modifying BA synthesis or dietary intake of ursodeoxycholic acid could improve tumor immunotherapy in liver cancer model systems.

Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.

Data on the effect on mucociliary clearance of oral high frequency oscillation is conflicting. By means of a technique to superimpose high frequency oscillation on tidal breathing, changes in mucociliary clearance during high frequency oscillation were studied in seven normal non-smokers by monitoring the clearance of inhaled radiolabelled aerosol from the lungs. After inhalation of 5 microns technetium 99m labelled particles under controlled conditions, whole lung clearance was monitored by scintillation counters half hourly for six hours with a final count at 24 hours, from which tracheobronchial deposition and clearance could be calculated. Control and high frequency oscillation studies were performed on separate days in random order. Oral high frequency oscillation was applied by a bass loudspeaker through a mouthpiece to superimpose sinewave oscillations (RMS input pressure 1.2 cm H2O, mean pressure zero) on normal breaths. On high frequency oscillation days 30 minutes of oscillation alternated with 30 min of rest. Between 3 and 4.5 hours mucociliary clearance with high frequency oscillation exceeded control by about 10% (p less than 0.05). The mean time taken to eliminate 90% of deposited radioaerosol from the tracheobronchial tree fell from 4 hours 50 minutes (range 1 h 52 min-6 h 50 min) during control to 3 hours 43 minutes (range 2 hr 28 min-5 hr 54 min) during the high frequency oscillation run (p less than 0.05). Possibly this comfortable, simple technique would be of therapeutic benefit to patients with chronic sputum retention and merits further investigation.