In This Issue

See article, p. 644.

High-dose IFNα2b for 1 year and ipilimumab for up to 3 years is the standard of care for high-risk resected melanoma, but it remains unknown if adjuvant anti–PD-1 therapy would improve overall survival (OS) of patients with this disease. Grossmann, Othus, Patel, and colleagues conducted a randomized phase III clinical trial that evaluated if adjuvant pembrolizumab improved recurrence-free survival (RFS) or OS as compared to the current standard of care. A significantly longer RFS was found in the pembrolizumab-treated group at the median follow-up of 47.5 months, but no significant change to OS was observed.

See article, p. 654.

Previous work suggests that high tumor mutational burden (TMB) may be associated with improved response rates to immunotherapy. Based on data from the MyPathway phase IIa multiple-basket study, Friedman and colleagues found that atezolizumab, an anti–PD-L1 antibody, had robust activity in an immunotherapy-naïve, tumor-agnostic population of patients with FoundationOne-assessed TMB ≥16 mut/Mb tumors, but not in patients with TMB ≥10 and <16 mut/Mb tumors (objective response rate of 38.1% vs. 2.1%, respectively, and disease control rate of 61.9% vs. 22.9%). Durable responses were observed in a variety of solid tumor types regardless of microsatellite instability status, PD-L1 expression level, and POLE/POLD1 mutation status.

See article, p. 670.

Intratumoral heterogeneity has hindered understanding of the gastric cancer tumor microenvironment. Kumar, Ramnarayanan, Sundar, Padmanabhan, and colleagues analyzed single-cell transcriptomes of over 200,000 cells from 31 patients to generate a comprehensive atlas of gastric cancer, representing various stages, histologic subtypes, and matched patient-derived organoids. Thirty-four distinct cell lineages were described, including novel cell populations. Using complementary experiments such as spatial transcriptomics, higher proportions of plasma cells in diffuse subtype gastric cancers were found and were associated with increased levels of epithelial-resident KLF2 and new INHBA–FAP-positive cancer-associated fibroblast subpopulations. The dataset forms a high-resolution molecular resource for the scientific community.

See article, p. 692.

Neuroendocrine carcinoma of the gastrointestinal system (GIS-NEC) is a rare and lethal form of cancer. Yachida, Totoki, Noë, Nakatani, Horie, and colleagues conducted a comprehensive genomic analysis using a large number of cases and indicated genomic differences between pancreatic NECs (Panc-NECs) and nonpancreatic GIS-NECs (Nonpanc-NECs). Panc-NECs could be classified into two subgroups (ductal-type and acinar-type) based on genomic features. Alterations in TP53 and RB1 proved common in GIS-NECs, while most Nonpanc-NECs with intact RB1 demonstrated mutually exclusive amplification of CCNE1. Transcription factors for neuroendocrine differentiation, especially the SOX2 gene, appeared overexpressed in most GIS-NECs due to hypermethylation of the promoter region.

See article, p. 712.

In a co–clinical trial of DIPG conducted by Izquierdo and colleagues, molecular profiling and drug screening of patient biopsy-derived avatars highlighted a sensitivity in vitro to the MEK inhibitor trametinib linked to distinct mutations in the MAPK pathway. Despite this, in vivo and clinical treatment failed to elicit significant single-agent responses. Generation of trametinib-resistant cells revealed MEK1/2 mutations as the underlying cause of resistance, with transcriptomic and proteomic profiling suggesting reciprocal sensitivity to the multikinase inhibitor dasatinib, confirmed in vitro and on ex vivo brain slices, suggesting a possible new combinatorial therapy for these children.

See article, p. 730.

High-risk neuroblastoma (NB) is an aggressive pediatric malignancy with poor overall survival. Durbin, Wang, and colleagues used CRISPR–Cas9 screens to show that NB cells exhibit selective dependency on the histone acetyltransferase EP300 compared with its paralog, CBP. Using a chemical biology strategy, a CRBN-binding degrader molecule was synthesized, called JQAD1, that degrades EP300 with minimal effects on CBP. JQAD1 caused genome-wide loss of enhancer acetylation and loss of transcription with early NB cell apoptosis in vitro and in murine xenografts. JQAD1 induced CRBN-dependent effects in a wide array of human tumor cell lines, suggesting a new therapeutic approach capitalizing on EP300-specific dependency.

See article, p. 752.

Approaches that alleviate the inhibitory constraints imposed on T cells by cell-surface checkpoints, such as PD-1, have revolutionized cancer management, but resistance is common. Wiede and colleagues report that the protein tyrosine phosphatase PTP1B restrains T-cell function and that its abundance is increased in intratumoral CD8⁺ T cells to limit T-cell antitumor immunity. The deletion or inhibition of PTP1B in endogenous or adoptively transferred T cells, including chimeric antigen receptor T cells, repressed tumor growth and enhanced the response to anti–PD-1 therapy. These findings identify PTP1B as an intracellular checkpoint and actionable drug target for cancer immunotherapy.

See article, p. 774.

Identifying mechanisms to induce cancer cell death is critical for improving clinical outcomes. Using unbiased CRISPR screening in leukemia cells to study the effect of ironomycin, Garciaz and colleagues observed that mitochondrial metabolism was the main modulator of ironomycin efficacy in acute myeloid leukemia cells. Using a multidisciplinary systems biology approach, the drug was found to induce strong depletion in mitochondrial iron, triggering a defect in mitochondrial respiration and a noncanonical BAX/BAK-dependent cell death process that was independent of caspase activation. This mechanism potentiated the effect of the BH3 mimetic venetoclax and resensitized venetoclax-resistant patient-derived leukemia cells.

See article, p. 792.

Differentiation blockade sustains the self-renewal of acute myeloid leukemia (AML) cells, while drivers of differentiation lead to arrest and represent potential therapeutic targets. Using CRISPR–Cas9 screening, Yan, Li, Milosevic, and colleagues identified the H3K9 histone acetyltransferase KAT6A as a driver of AML differentiation arrest. Inhibition of KAT6A reduced self-renewal and proliferation in AML cells and extended survival in MLL-rearranged mouse models. Mechanistically, KAT6A catalyzes H3K9ac at promoters of AML oncogenes such as MYC, allowing recruitment of the H3K9ac “reader” protein ENL, which promotes transcriptional elongation to maintain high levels of oncogene expression. These findings implicate KAT6A and ENL as potential targets for AML differentiation therapy.

See article, p. 812.

Isocitrate dehydrogenase 1 mutations (mIDH1) are common in several malignancies, including cholangiocarcinoma, and cause generation of (R)-2-hydroxyglutarate [(R)-2HG]. Wu, Shi, Dubrot, and colleagues showed that the efficacy of the mIDH1 inhibitor ivosidenib in a mouse model of intrahepatic cholangiocarcinoma is mediated by dual mechanisms stimulating antitumor immunity. CD8⁺ T cells are recruited and induced to produce IFNγ. In turn, ivosidenib restores the ability of the tumor cells to respond to IFNγ by activating the TET2 demethylase [an (R)-2HG target], thereby epigenetically upregulating IFNγ target genes. While immune checkpoint activation eventually promotes tumor progression, combined ivosidenib and anti-CTLA4 treatment shows potent synergy.

See article, p. 836.

Splicing factor (SF) mutations in cancers have been associated with transcriptome-wide splicing alterations, but alterations that are direct consequences of these mutations remain elusive in the absence of RNA/protein interaction data. Wheeler, Vora, and colleagues integrated splicing analyses with RNA binding using eCLIP in isogenic human induced pluripotent stem cell models of SRSF2^P95L- and U2AF1^S34F-mutated myelodysplastic syndrome. Both mutations increased binding of the SFs to exon 3 of GNAS, promoting a long isoform, which encodes a more active form of the G protein subunit Gas. This activates ERK and renders SF-mutant cells sensitive to MEK inhibition.

See article, p. 856.

Early T-cell acute lymphoblastic leukemia (ETP-ALL) is an aggressive form of leukemia with stem cell features and poor prognosis. Rashkovan and colleagues performed metabolic profiling of ETP-ALL patient samples revealing a distinct metabolic wiring and a selective dependency on the mevalonate biosynthesis pathway. Additionally, pharmacologic inhibition of cholesterol biosynthesis with statins suppressed ETP leukemia cell growth via inhibition of AKT1 signaling and epigenetic downregulation of MYC expression. These findings establish a previously unrecognized role for cholesterol intracellular pools and the mevalonate pathway in the control of oncogenic signaling and epigenetic circuitries driving leukemia cell growth and survival.