Volume 539 Number 7629

Editorials

Fed up of Earth? Try Mars p.330

Establishing a Martian outpost is likely to bring many of the same societal problems we face on Earth.

doi: 10.1038/539330b

News

News Features

News & Views

Clear directions for random lasers p.360

Random lasers use disordered structures to produce light, which is usually emitted in many directions. A random laser that can produce a collimated beam offers a wide range of applications, from imaging to security scanning.

doi: 10.1038/nature20477

Mature proteins braced by a chaperone p.361

Hsp70 chaperone molecules help other proteins to fold, and were thought to bind mainly to unfolded proteins. Single-molecule experiments now suggest that Hsp70s can also stabilize almost fully folded proteins. See Letter p.448

doi: 10.1038/nature20470

Ions surprise in Earth's deep fluids p.362

Models indicate that there are strong gradients in element concentrations and in the pH of fluids at the slab–mantle interface — a major discontinuity deep within Earth. This transforms our view of global geochemical transport. See Letter p.420

doi: 10.1038/539362a

Sleepy and dreamless mutant mice p.364

Sleep in mammals consists of non-rapid-eye-movement and rapid-eye-movement sleep. A large genetic screen reveals that these two sleep states are altered in mice by mutations dubbed Sleepy and Dreamless. See Article p.378

doi: 10.1038/nature20471

Semiconductors that stretch and heal p.365

Polymeric semiconductors have been prepared whose molecular properties make them stretchable and healable — a milestone in the development of sophisticated organic electronic surfaces that mimic human skin. See Letter p.411

doi: 10.1038/539365a

Deep-sea secrets of butane metabolism p.367

Anaerobic microbes have been found to break down the hydrocarbon butane by a pathway with some similarities to anaerobic methane breakdown. Harnessing the butane pathway might enable biofuel generation. See Article p.396

doi: 10.1038/539367a

Review

Articles

Letters

PI3Kγ is a molecular switch that controls immune suppression p.437

Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.

doi: 10.1038/nature19834

Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells p.443

Recent clinical trials using immunotherapy have demonstrated its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies against cytotoxic-T-lymphocyte-associated protein 4 or programmed cell death protein 1/programmed death-ligand 1 have displayed durable clinical responses in various cancers. Although these new immunotherapies have had a notable effect on cancer treatment, multiple mechanisms of immune resistance exist in tumours. Among the key mechanisms, myeloid cells have a major role in limiting effective tumour immunity. Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance. These observations suggest a need for a precision medicine approach in which the design of the immunotherapeutic combination is modified on the basis of the tumour immune landscape to overcome such resistance mechanisms. Here we employ a pre-clinical mouse model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumours. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3Kγ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3Kγ with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumour immune microenvironment and promote cytotoxic-T-cell-mediated tumour regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3Kγ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumours.

doi: 10.1038/nature20554