Cancer cells express tumour-specific antigens derived via genetic and epigenetic alterations, which may be targeted by T-cell-mediated immune responses. However, cancer cells can avoid immune surveillance by suppressing immunity through activation of specific inhibitory signalling pathways, referred to as immune checkpoints. In recent years, the blockade of checkpoint molecules such as PD-1, PD-L1 and CTLA-4, with monoclonal antibodies has enabled the development of breakthrough therapies in oncology, and four therapeutic antibodies targeting these checkpoint molecules have been approved by the FDA for the treatment of several types of cancer. Here, we report the crystal structures of checkpoint molecules in complex with the Fab fragments of therapeutic antibodies, including PD-1/pembrolizumab, PD-1/nivolumab, PD-L1/BMS-936559 and CTLA-4/tremelimumab. These complex structures elucidate the precise epitopes of the antibodies and the molecular mechanisms underlying checkpoint blockade, providing useful information for the improvement of monoclonal antibodies capable of attenuating checkpoint signalling for the treatment of cancer.

Background The health impacts of wildfire smoke, including fine particles (PM2.5), are not well understood and may differ from those of PM2.5 from other sources due to differences in concentrations and chemical composition. Methods First, for the entire Western US (561 counties) for 2004–2009, we estimated daily PM2.5 concentrations directly attributable to wildfires (wildfires-specific PM2.5), using a global chemical transport model. Second, we defined smoke wave as ≥2 consecutive days with daily wildfire-specific PM2.5>20µg/m3, with sensitivity analysis considering 23µg/m3, 28µg/m3, and 37µg/m3. Third, we estimated the risk of cardiovascular and respiratory hospital admissions associated with smoke waves for Medicare enrollees. We used a generalized linear mixed model to estimate the relative risk of hospital admissions on smoke wave days compared to matched comparison days without wildfire smoke. Results We estimated that about 46 million people of all ages were exposed to at least one smoke wave during 2004 to 2009 in the Western US. Of these, 5 million are Medicare enrollees (≥65y). We found a 7.2% (95% confidence interval: 0.25%, 15%) increase in risk of respiratory admissions during smoke wave days with high wildfire-specific PM2.5 (>37µg/m3) compared to matched non-smoke-wave days. We did not observe an association between smoke wave days with wildfire-PM2.5≤37µg/m3 and respiratory or cardiovascular admissions. Respiratory effects of wildfire-specific PM2.5 may be stronger than that of PM2.5 from other sources. Conclusion Short-term exposure to wildfire-specific PM2.5 was associated with risk of respiratory diseases in the elderly population in the Western US during severe smoke days.