Tumoural activation of TLR3–SLIT2 axis in endothelium drives metastasis
How endothelial cells aid in the dissemination of cancer is not well-known. By assessing highly and poorly metastatic tumors, Tavora et al. identify the specific compartment within the endothelium that contributes to metastases based on expression of Slit2. Expression of SLIT2 protein by endothelial cells, in addition to its receptor, promotes migration and invasion of lung and breast cancer cells, and Slit2 deletion in endothelial cells, but not tumor cells, reduces metastasis in mouse models. Mechanistically, tumor-derived double-stranded RNA triggers endothelial SLIT2 protein expression via TLR3 signaling. The data highlight an important role of endothelial cells in facilitating metastases and how the expression of Slit2, as well as its cellular source, can dictate disease progression.
Interleukin-17–induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) has an immunosuppressive tumor microenvironment (TME) that contributes to therapy resistance. Zhang et al. find that IL17 plays a pivotal role in maintaining immune suppression in the PDAC TME by recruiting neutrophils and subsequent induction of neutrophil extracellular traps (NET) via their upregulation of peptidyl arginine deiminase type IV (Padi4). At the same time, CD8+ T-cell recruitment and activation are decreased when IL17 is present. By blocking IL17 signaling, tumors are sensitized to immune checkpoint blockade, an effect dependent on CD8+ T cells. In patients, high IL17 and PADI4 expression correlates with poor prognosis, thus, blocking IL17 could boost antitumor responses in PDAC.
Single-cell analyses identify brain mural cells expressing CD19 as potential off-tumor targets for CAR-T immunotherapies
Neurologic toxicities are a known adverse event associated with chimeric antigen receptor (CAR) T-cell therapy, but the mechanisms underlying these are not well known. CD19 is typically considered a B cell–specific marker, and its targeting has been the basis for some CAR T-cell therapies. Parker et al., through single-cell RNA sequencing, show that CD19 is also expressed in human brain mural cells, which have a vital role in maintaining the integrity of the blood–brain barrier. CD19 expression by brain mural cells occurs during their development and is maintained across the brain. These data show how mural cell CD19 expression could account for, or at least contribute to, the neurotoxicities associated with CD19-directed therapies.
IL4I1 is a metabolic immune checkpoint that activates the AHR and promotes tumor progression
The aryl hydrocarbon receptor (AHR), which regulates immune function, is a transcription factor activated by ligands such as tryptophan derivatives. Using a pan-tissue AHR signature, Sadik et al. identify IL4I1 as a potent AHR-activating enzyme. IL4I1, like IDO1, catabolizes tryptophan, but it generates indole-3-pyruvic acid, which gives rise to AHR ligands. IL4I1 is highly expressed in primary and metastatic human tumors, with its expression positively correlating with myeloid-derived suppressor cells and regulatory T cells. This effect of IL4I1 enhances chronic lymphocytic leukemia progression in mice. IL4I1 expression is increased together with IDO1 expression after immune checkpoint blockade (ICB), and this may induce resistance to ICB and to combination ICB and IDO inhibition.
Functional genomic landscape of cancer-intrinsic evasion of killing by T cells
A comprehensive understanding of the genes and pathways that allow cancer cells to evade the immune system is still lacking. Using a genome-wide CRISPR screen, Lawson et al. identify a core set of 182 cancer cell–intrinsic genes associated with evasion from killing by CTLs across a panel of six mouse cancer cell lines. Analysis of the dataset reveals discrete functional modules of genes that mediate resistance to killing by CTLs. One module shows that the autophagy pathway mediates cancer cell evasion of CTL-induced cytotoxicity by IFNγ and TNF. The data strengthen our understanding of the interplay between cancer and the immune system.
Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy
Certain species of intestinal bacteria are associated with increased immune checkpoint blockade (ICB) efficacy; what mediates these effects is unclear. Mager et al. show that ICB efficacy in mouse models of colorectal cancer is enhanced by intestinal Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species, all of which are found in human intestines. B. pseudolongum mediates its effects through production of inosine, which enters the blood and promotes Th1 cell differentiation. The ICB-enhancing effect of inosine is context dependent, requiring costimulation, and also occurs in models of bladder cancer and melanoma, suggesting new avenues for developing ICB-enhancing therapies.