Highlights from Recent Cancer Literature

A current limitation of the effectiveness of immunotherapies has toxic effects on the immune system in noncancerous tissues. To identify immune pathways unique to tumors, Mair and colleagues compared immune phenotypes in human head and neck squamous cell carcinomas (HNSCC) with inflamed surrounding oral mucosal tissue and with peripheral blood immune cells, using flow cytometry, single cell transcriptomics, and the NicheNet ligand-receptor analysis tool for cell-cell interactions. First, they found tremendous congruence between immune cells in tumor tissues compared with cells in inflamed nontumor tissues. Second, they discovered that IL1R1 and the previously defined marker ICOS were almost exclusively induced on tumor-infiltrating regulatory T cells (Treg). Third, they found that IL1R1+ Tregs were highly suppressive. IL1R1 was induced on Tregs acutely, therefore its expression in tumors was likely a consequence of the high activation state of Tregs in tumors. Further, Tregs expressed high levels of the chemokine receptor CXCR6. Its ligand (CXCL16) was highly expressed from monocytes and dendritic cells, specifically in HNSCC. Finally, IL1R1+ICOS+ Tregs were enriched in human papillary, breast, and lung cancers, establishing this Treg phenotype across multiple cancer types.Expert Commentary: This study identified that IL1R1 expression defines highly suppressive tumor-infiltrating Tregs and highlighted similarities between the tumor microenvironment and inflamed normal tissues.Mair F, Erickson JR, Frutoso M, Konecny AJ, Greene E, Voillet V, et al. Extricating human tumour immune alterations from tissue inflammation. Nature 2022;605:728–35.Although EGFR tyrosine kinase inhibitors (TKI) treatment results in a significant response in most patients with EGFR mutant non-small cell lung cancer (NSCLC), de novo resistance is seen in 20%–30% of patients. Nanjo and colleagues demonstrated that co-occurring RBM10 mutations lead to suppression of apoptosis and EGFR TKI resistance. EGFR mutant NSCLC patients with co-occurring RBM10 mutations had shorter progression-free survival and a lower response rate. RBM10 deficiency shifted the Bcl-x transcript toward the longer antiapoptotic form Bcl-xL, resulting in resistance, which could be reversed with the addition of a Bcl-xL inhibitor.Expert Commentary: This study demonstrated that co-occurring RBM10 mutations can confer EGFR TKI resistance and represent a potentially targetable subset of patients in the clinic.Nanjo S, Wu W, Karachaliou N, Blakely CM, Suzuki J, Chou Y-T, et al. Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR mutant lung cancer. The Journal of Clinical Investigation; Published online May 17, 2022; doi: 10.1172/JCI145099.The mortality rate in patients with noninvasive lesions in their breast, such as ductal carcinoma in situ (DCIS), has remained unchanged even after surgery and radiotherapy. A significant percentage of these women never progress locally, yet still die from distant recurrence. Rodriguez-Tirado and colleagues reported that the orphan nuclear receptor NR2F1/COUP-TF1 serves as a barrier to early dissemination. NR2F1 downregulation in HER2+ early-stage cancer cells resulted in disorganized laminin V, reduced E-cadherin expression, activation of the β-catenin signaling, and increased expression of EMT genes. Downregulation of NR2F1 also promoted a hybrid luminal/basal phenotype. High-resolution intravital imaging revealed that loss of NR2F1 in HER2+ DCIS favored in vivo motility and invasion without increasing cancer cell proliferation.Expert Commentary: In patients with DCIS, HER2-mediated suppression of NR2F1 represents a crucial mechanism by which early tumor cells can gain increased invasive properties.Rodriguez-Tirado D, Kale N, Carlini MJ, Shrivastava N, Rodrigues AA, Khalil BD, et al. NR2F1 is a barrier to dissemination of early-stage breast cancer cells. Cancer Res 2022;82:2313–26.Protein methyltransferases (PRMT) catalyze methylation of arginine and are critical mediators of leukemic stem cell (LSC) survival and self-renewal in chronic myelogenous leukemia (CML). Liu and colleagues defined a role for PRMT7 in LSCs by developing hematopoietic cell–specific PRMT7 knockout mice. Genetic deletion of PRMT7 delayed development of CML (with minimal effects on normal hemoatopoiesis) in bone marrow cells transduced with BCR-ABL retroviruses. Loss of PRMT7 reduced LSC growth and self-renewal in a methyltransferase-dependent manner. The authors went on to design and synthesize JS1310, a selective small-molecule inhibitor of PRMT7. Inhibition of PRMT7 by shRNA or use of JS1310 inhibited self-renewal and growth of human CML cells. Loss of PRMT7 reprogrammed glycine metabolism by downregulating expression of glycine decarboxylase in CML LSCs, resulting in accumulation of the toxic metabolite methylglyoxal.Expert Commentary: This study provides rationale and compelling data that the protein methyltransferase PRMT7 is a selective and druggable vulnerability in LSCs that can eliminate LSCs and prolong survival of CML mice.Liu C, Zou W, Nie D, Li S, Duan C, Zhou M, et al. Loss of PRMT7 reprograms glycine metabolism to selectively eradicate leukemia stem cells in CML. Cell Metabolism; Published online May 3, 2022; doi: 10.1016/j.cmet.2022.04.004.ERK1/2 is a critical effector in human cancers and specifically in JAK2V617F-driven myeloproliferative neoplasms (MPN). Active site inhibitors of ERK1/2 have alleviated but not eliminated MPNs. Zhang and colleagues performed a structure function study, demonstrating opposing roles for substrate binding domains D and DBP of ERK2 (pro-oncogenic and antioncogenic, respectively) in the pathogenesis of JAK2V617F-driven MPNs. The literature shows that this is not the case in melanoma, suggesting context-dependent functions. Most ERK substrates including p90RSK are D-domain substrates. The ERK2-Egr1 substrate interaction via the DBP domain was important for antioncogenic roles of ERK2 in MPNs involving oncogene-induced senescence. Pharmacological inhibition of the D-domain and not the DBP domain or active site spared ERK phosphorylation, Egr1 interaction, and blocked growth of ERK-dependent MPN cells via inhibition of D-domain specific substrates.Expert Commentary: Targeting the ERK-substrate interaction D-domain holds potential as a more effective alternative to active site inhibitors. Resolving context-dependent roles of kinases in cancer may come down to the activities of substrate domains.Zhang Y, Truong B, Fahl SP, Martinez E, Cai K, Dulaimi E, et al. The ERK2 DBP domain opposes pathogenesis of a JAK2V617F-driven myeloproliferative neoplasm. Blood; Published online April 18, 2022; doi.org/10.1182/blood.2021013068.Monocytes, which include brain-resident microglia and peripheral blood–derived macrophages, comprise a significant fraction of the brain tumor microenvironment and can contribute to poor outcomes in patients with brain tumors. Huang and colleagues seeded monocyte-depleted mouse brain slices with human glioblastoma cells in combination with microglia derived from human-induced pluripotent stem cells. Implantation of both cell types together enhanced tumor growth. Glioblastoma cells stimulated microglia and other monocytes to produce CCL18, a gene without a murine ortholog. CCL18 then enhanced cancer cell growth and migration via a signaling cascade that activated Akt.Expert Commentary: This study presents a useful model system—organotypic brain slices seeded with human microglia generated in vitro—as well as adding to the list of secreted factors involved in cross-talk between brain tumor cells and immune cells. Whether factors that drive monocytes to produce CCL18 also affect other immune cell types, and whether these cells in turn impact tumor growth, remains to be shown.Huang Y, Motta E, Nanvuma C, Kuhrt LD, Yuan Y, Xia P, et al. Microglia/macrophage-derived human CCL18 promotes glioma progression via CCR8-ACP5 axis analyzed in humanized slice model. Cell Rep 2022;39:110670. doi: 10.1016/j.celrep.2022.110670.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.