A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors.

Abstract

TIM-3 blockade leads to increased DNA sensing by cGAS–STING (by Kissiovd via Wikimedia Commons)TIM-3 blocking antibodies, which are showing promise in cancer clinical trials, can reverse T-cell exhaustion, but their effects on other immune cells are less clear. de Mingo Pulido et al. show that blocking TIM-3 promotes HMGB1-dependent endocytosis of extracellular DNA by classical dendritic cells. This activates the cyclic GMP-AMP synthase (cGAS) and stimulator of IFN genes (STING) pathway, leading to type I IFN and subsequently CXCL9 production. This pathway is required for the antitumor effects of TIM-3 blockade and paclitaxel in a mouse breast cancer model. The study provides new understanding of the mechanisms underlying TIM-3–targeted therapy.de Mingo Pulido Á, …, Ruffell B. Immunity 2021 Jun 8;54:1154–67.e7.TRMs in the lungs provide a niche that promotes tumor progression (from Nephron via Wikimedia Commons)Increased understanding of the diversity of macrophages in tumors is needed to effectively target the cells therapeutically. Using single-cell RNA sequencing, Casanova-Acebes et al. find four myeloid populations in human non–small cell lung carcinoma and in a mouse model of lung adenocarcinoma. The tissue-resident macrophage (TRM) population is reduced in mouse and human tumors compared with normal lung tissues. TRMs accumulate close to tumor cells early in tumor formation, promoting epithelial–mesenchymal transition, tumor-cell invasiveness, and regulatory T-cell responses. The data identify TRMs as potential targets for preventing and treating early-stage lung cancer.Casanova-Acebes M, …, Merad M. Nature 2021 Jun 16. DOI: 10.1038/s41586-021-03651-8.CD8+ TIL function is impaired by uptake of oxidized lipids via CD36 (from Victor A. Drover via Wikipedia)Lipid accumulation is a common metabolic characteristic of the tumor microenvironment (TME). Xu et al. show that oxidized lipids are prevalent in the TME in two mouse tumor models. Oxidized lipids are taken up by CD8+ tumor-infiltrating lymphocytes (TIL) via CD36, which is expressed at elevated levels on terminally exhausted PD-1+TIM-3+CD8+ TILs. Uptake of oxidized lipids induces lipid peroxidation and p38 MAPK activation, which reduces IFNγ and TNF production. Ablation of Cd36 and overexpression of glutathione peroxidase 4 (GPX4), which suppresses lipid peroxidation, restore CD8+ TIL function, highlighting the potential for targeting this pathway for cancer immunotherapy.Xu S, …, Kaech SM. Immunity 2021 Jul 13;54:1561–77.e7.ILC2s are a new potential therapeutic target in melanoma (by Julio C. Valencia, NCI Center for Cancer Research)Group 2 innate lymphoid cells (ILC2) in the skin can have both protumorigenic and antitumorigenic properties, but their effects in the melanoma tumor microenvironment (TME) are not well-known. Jacquelot et al. show that ILC2s infiltrate melanomas and are associated with a favorable prognosis in patients. In mouse models, ILC2-derived GM-CSF recruits eosinophils into the TME, boosting antitumor responses. However, infiltrating ILC2s also express PD-1, contributing to immunosuppression. Blockade of PD-1 in combination with IL33, an activating cytokine, unleashes ILC2/eosinophil antitumor immunity in the TME. The data highlight the potential to target ILC2s in melanoma to improve antitumor responses.Jacquelot N, …, Belz GT. Nat Immunol 2021 Jul 1;22:851–64.The liver microenvironment can switch on and off dormant tumor cells (by Firstfreddy via Wikimedia Commons)How disseminated tumor cells “turn on” after dormancy to seed metastases remains unclear. Correia et al. demonstrate a key role for NK cells in preventing breast tumor cells from exiting dormancy and forming metastases in the liver. Administration of IL15 maintains IFNγ in the microenvironment and is required for keeping tumor cells in a dormant state. A reduction in NK cells in the liver, as well as a concurrent accumulation of activated hepatic stellate cells (HSC), precedes tumor-cell exit from dormancy. This process is mediated by HSC-derived CXCL12, which induces NK-cell quiescence through interactions with CXCR4. The study provides insight into how tissue environments can permit or prevent progression of metastases.Correia AL, …, Bentires-Alj M. Nature 2021 Jun 2;594:566–71.Tregs in the TME can self-regulate via a feedback loop (photo by A. Benavides)How regulatory T cells (Treg) are regulated in the tumor microenvironment (TME) is not fully understood. Marangoni et al. find that conventional dendritic cells (cDC) in the TME can present tumor-associated antigens to pre-enriched polyclonal Tregs. These Tregs are maintained in the TME via transient T-cell receptor signals received during short-lived, unstable interactions with cDCs, a process maintained by a CTLA-4–dependent feedback loop that regulates Treg activation and proliferation via CD28. Blockade of CTLA-4 stabilizes Treg–cDC interactions, promoting Treg expansion. The data highlight that further intervention may be needed during immune checkpoint blockade of CTLA-4 so that immune-suppressive cell types are not promoted.Marangoni F, …, Mempel TR. Cell 2021 Jun 21. DOI: 10.1016/j.cell.2021.05.027.