Melanoma, a skin cancer associated with high mortality rates, is highly radio- and chemotherapy resistant but can also be very immunogenic. These circumstances have led to a recent surge in research into therapies aiming to boost anti-tumor immune responses in cancer patients. Among these immunotherapies, neutralizing antibodies targeting the immune checkpoints T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are being hailed as particularly successful. These antibodies have resulted in dramatic improvements in disease outcome and are now clinically approved in many countries. However, the majority of advanced stage melanoma patients do not respond or will relapse, and the hunt for the "magic bullet" to treat the disease continues. This review examines the mechanisms of action and the limitations of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies which are the two types of checkpoint inhibitors currently available to patients and further explores the future avenues of their use in melanoma and other cancers.

Tissue macrophages have a split personality: Resident tissue macrophages (RTMs) reside in various tissue-specific niches during development. They evince microenvironment-directed phenotypes that support host defense and tissue homeostasis. Chakarov et al. used single-cell RNA sequencing and fate-mapping of murine lung RTMs to interrogate RTM-subset heterogeneity, interrelationships, and ontogeny (see the Perspective by Mildner and Yona). In addition to alveolar macrophages, they identified two different interstitial macrophage populations. One population mostly abutted nerve fibers; the other population preferentially localized near blood vessels and appeared to support vessel integrity and inhibit inflammatory cell infiltration into tissues. Science , this issue p. eaau0964 ; see also p. 1154

Allergic asthma is caused by the aberrant expansion in the lung of T helper cells that produce type 2 (T _H 2) cytokines and is characterized by infiltration of eosinophils and bronchial hyperreactivity. This disease is often triggered by mast cells activated by immunoglobulin E (IgE)–mediated allergic challenge. Activated mast cells release various chemical mediators, including prostaglandin D ₂ (PGD ₂ ), whose role in allergic asthma has now been investigated by the generation of mice deficient in the PGD receptor (DP). Sensitization and aerosol challenge of the homozygous mutant (DP ^−/− ) mice with ovalbumin (OVA) induced increases in the serum concentration of IgE similar to those in wild-type mice subjected to this model of asthma. However, the concentrations of T _H 2 cytokines and the extent of lymphocyte accumulation in the lung of OVA-challenged DP ^−/− mice were greatly reduced compared with those in wild-type animals. Moreover, DP ^−/− mice showed only marginal infiltration of eosinophils and failed to develop airway hyperreactivity. Thus, PGD ₂ functions as a mast cell–derived mediator to trigger asthmatic responses.