Nesteene J. Param

Sex-dependent immune responses in NOTCH1-driven liver tumors

NOTCH1-driven tumors in females lead to impaired CD8+ T cell priming and activation

Mechanism of immune surveillance in males with NOTCH1 liver tumors

Enhancing DC-T cell axis in females harboring NOTCH1-driven tumors has therapeutic effects

Hepatocellular carcinoma presents strong sexual dimorphism, being two to three times more frequent in males than in females; however, the role of sex in response to immunotherapies in HCC remains unknown. We demonstrate that NOTCH1, an understudied oncogene in HCC, elicits sexually dimorphic antitumor immunity and response to FDA-approved immunotherapies. Surprisingly, males harboring NOTCH1-driven tumors displayed enhanced antitumor immune responses, which, in mice, were mediated by dendritic and T cells. Conversely, females harboring NOTCH1-driven tumors presented immune evasion and resistance to immunotherapies through a defect in dendritic cell (DC)–mediated priming and activation of CD8+ T cells in mice, which was restored therapeutically with CD40 agonism. Mechanistically, the sexually dimorphic immunity was mediated by genes in the sex chromosomes but not by sex hormones. Together, our study unravels an unexpected association between NOTCH1 and sex in cancer immunity and highlights the potential of restoring the DC−CD8+ T-cell axis with CD40 agonism to improve outcomes.Significance:Although HCC presents strong sexual dimorphism, the role of sex in response to immunotherapies remains elusive. With a novel HCC mouse model and validation in patients with HCC, we demonstrate that NOTCH1 disrupts antitumor immunity specifically in females through a mechanism mediated by sex chromosome genes, which is reversed with CD40 agonism.See related commentary by Zhu and Koltsova, p. 452

Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by abnormal proliferation and differentiation of blasts. PRMT5, a methyltransferase that catalyzes symmetric dimethylation of arginine (SDMA) residues, has been implicated in cancer stem cell homeostasis and shown to be a potential therapeutic target in AML. However, given the toxicity of complete PRMT5 inhibition, there is a need to identify effective synergistic therapies. Through a targeted screen of compounds that inhibit key nodes of PRMT5-regulated pathways, we identified a synthetic lethality between inhibition of PRMT5 and LSD1, a lysine demethylase known to affect AML blast differentiation. The two inhibitors broadly reshape the transcriptome of targeted cells and synergize to promote AML differentiation and eventually growth inhibition and apoptosis, in a p53-dependent manner. To leverage this synthetic lethal interaction, we generated new dual compounds to inhibit both enzymes and recapitulated the effects of the drug combination. Our results uncover an unexpected convergence of PRMT5- and LSD1-regulated targets, paving the way for new therapeutic opportunities.

Supplemental Figure 6.Cell survival of GIST T1 cells treated with imatinib or avapritinib for 72h in complete media.Each data point represents an average of 10 wells.

Supplemental Figure 8. Relative MYLK mRNA expression by qPCR in GIST PDGFRA D842V PDXs treated with vehicle(Veh) or imatinib (IM) for 2 weeks.

Supplemental Figure 3. GIST PDGFRA D842V PDXs are not sensitive to crenolanib.