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Grockowiak et al. explore bone marrow niche heterogeneity in myeloproliferative neoplasms, polycytemia vera and essential thrombocytemia and find JAK2-mutated hematopoietic stem cells occupying distinct niches affecting cell growth and therapy response.
Wu et al. show that versions of IL-2 that preserve CD25 activity expand tumor-specific T cells more effectively than CD25-sparing agonists and find that the efficacy of anti-PD-1 depends on the activation of PD-1+CD25+ T cells through autocrine IL-2 signaling.
Wang and colleagues generate two protein-level mutant p53 reporters and use them to identify precancerous clones in normal tissues in vivo, characterized by increased amino acid metabolism and a transcriptomic signature that includes Ybx3.
Guccione and colleagues identify and characterize a sorafenib derivative, WNTinib, with therapeutic efficacy in β-catenin-mutated hepatocellular carcinoma and identify EZH2 as important for the activity of the inhibitor.
Fecci and colleagues show that tumor cells having lost MHC-I, a major mechanism of immune escape, are amenable to killing by CD8+ T cells through an MHC-I-independent, alternative pathway via NKG2D and NKG2DL interaction and granzyme.
Roesch and colleagues use clinical datasets and mouse models of BRAF-mutant melanoma to reveal a role for IL-17A in positive responses to anti-PD-1 and anti-CTLA-4 therapy, which they also link to infiltrating neutrophils.
Wang and colleagues perform single-cell profiling of human ovarian cancer samples from five anatomic sites, revealing dynamics of the immune microenvironment in malignant ascites and cell subtypes that may play a role in chemotherapy response.
Lynch and colleagues characterize γδ T cells in colorectal and endometrial cancer and identify distinct subsets with opposing cytotoxic and wound healing functions, leading them to develop an expansion method that enhances cytotoxic functions.
Alimonti and colleagues show that coordinated activation of the Akt/mTOR and MNK/eIF4E pathways rewires the prostate cancer translatome to secrete HGF, SPP1 and BGN and recruit suppressive myeloid cells, which can be therapeutically targeted.
Jia and colleagues profile human glioblastoma samples and identify a population of macrophages characterized by Siglec-9 that drives immune evasion and immunotherapy resistance via restriction of T-cell priming. Their therapeutic elimination synergizes with immunotherapy.
Mota et al. show that poor response to immune checkpoint blockade in mouse models of ALK-rearranged NSCLC can be overcome by vaccination with an immunogenic ALK peptide and identify immunogenic human ALK peptides for future translational study.
Using genetically engineered models, Genovese and colleagues study patterns of convergent evolution in renal cancer, and pinpoint dysregulation of interferon signaling as a means of adaptation to chromosomal instability in metastatic progression.
Xiong et al. engineer CAR T cells to express the c-Kit D816V mutation, which enhances antigen-dependent proliferation and cytotoxicity, translates into extended survival in solid tumor models and is controllable by tyrosine kinase inhibitors.
Zhou et. al. report the interim results of the randomized phase III GEMSTONE-302 trial, showing the overall survival benefits of first-line treatment with the PD-L1 inhibitor sugemalimab versus placebo in combination with chemotherapy, in patients with NSCLC.
Sung et. al. identify genetic, molecular and clinical risk factors for immune-related adverse events in multicancer cohorts of patients treated with checkpoint inhibitors and develop predictive models that they validate in an independent cohort.
Adachi et al. describe a mechanism of adaptive resistance to KRAS G12C inhibitors which involves a Scribble mis-localization via palmitoylation and subsequent YAP and MRAS activation that leads to feedback reactivation of MAPK signaling.
Hagenbeek et al. identify a small-molecule pan-TEAD inhibitor that blocks the interaction between YAP/TAZ and TEAD proteins. They demonstrate that treatment with the inhibitor leads to antitumor activity and can synergize with KRAS G12C inhibition.
Malladi and colleagues show that inhibiting DRP1 limits mitochondrial plasticity, resulting in increased mitochondrial fusion, impaired fatty acid oxidation and reduced metastasis formation in breast cancer models.
Bousso and colleagues show that IFN-γ production is the dominant tumor elimination mechanism exerted by CD4+ CAR T cells and define tumor cell sensitivity to IFN-γ as a determinant of CD4+ CAR T efficacy.
Merbl and colleagues demonstrate that high expression of the proteasome regulator PSME4 is associated with immune-cold lung tumors and reduced antitumor immune responses, by functioning to modulate the protein degradome and antigen diversity.