Volume 19 Issue 3, March 2019

Cancer brings an increasing health and economic burden worldwide, and the greatest impact is had on the most vulnerable populations. In this Comment, Christopher Wild discusses the need for investment to ensure long-term cancer prevention strategies.

Gkountela et al. have identified that circulating tumour cell (CTC) clusters from patients and mouse models with breast cancer have a distinct DNA methylation profile from that of single CTCs, which together with the phenotypic difference represent a targetable therapeutic vulnerability of metastasis.

Laumont, Vincent et al. have developed a proteogenomic strategy for high-throughput mass spectrometry-based discovery of aberrantly expressed tumour-specific antigens from non-coding sequences as well as mutated tumour-specific antigens encoded by all genomic regions, thereby expanding the number of targetable antigens that can be used for cancer vaccine development.

Neal et al. have successfully established patient-derived organoids of tumour epithelia retaining native immune cells, thereby recapitulating tumour microenvironment diversity and enabling immuno-oncology studies.

Keklikoglou et al. show that, in mouse models of chemoresistant breast cancer, paclitaxel and doxorubicin trigger the production of tumour-derived extracellular vesicles with pro-metastatic properties that are dependent on annexin A6.

Ruscetti, Leibold, Bott et al. show that the growth of Kras-mutant lung tumours is sensitive to combined blockade of KRAS effectors. This was dependent on induction of the senescence-activated phenotype in cancer cells, followed by natural killer cell-mediated cell clearance.

A new study has shown that endovascular progenitor cells, which are precursors of the endothelial cells that make up tumour blood vessels, are inhibited by conditional ablation of Notch signalling, leading to inhibition of melanoma metastasis in mice.

Two phase I studies, recently published in Nature, show that the administration of personalized vaccines to newly diagnosed patients with glioblastoma generates tumour-reactive T cells that infiltrate glioblastomas, turning them into ‘hot’ tumours potentially susceptible to further immunotherapy approaches.

Two studies show that cancer cells contain sufficient quantities of immunostimulatory nucleic acids to trigger interferon signalling, increase antitumour immunity and overcome resistance to checkpoint blockade. Loss of the RNA-editing enzyme ADAR1 enables tumour cells to sense these innate ligands.

This Review discusses recent work demonstrating that immune checkpoint inhibitor efficacy is affected by a combination of factors involving tumour genomics, host germline genetics, programmed cell death 1 ligand 1 (PDL1) levels and other features of the tumour microenvironment, as well as the gut microbiome.

In this Review, Jones et al. present the evidence that epigenetic therapies can induce the expression of endogenous retroviruses and cancer–testis antigens normally silenced by DNA methylation in most somatic cells. As a consequence, a state of viral mimicry is evoked in cancer cells, leading to an innate immune response. Understanding this process has implications for combination therapy with epigenetic drugs and immunotherapies to improve clinical outcomes for patients with cancer.

This Review discusses how increased catabolism of the amino acids tryptophan and arginine driven by inflammatory processes in the tumour microenvironment contributes to tumorigenesis, suppression of antitumour immunity and potentially neurological comorbidities associated with cancer.