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NOTCH1 Drives Sexually Dimorphic Immune Responses in Hepatocellular Carcinoma
Katherine E Lindblad1,2,3,4, Romain Donne1,2,3, Ian Liebling1,2,3
1The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
NOTCH1 oncogene impacts antitumor immunity differently in males and females with hepatocellular carcinoma (HCC). This study reveals NOTCH1 disrupts female immune response, a defect reversed by CD40 agonism.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Hepatocellular carcinoma (HCC) exhibits significant sexual dimorphism, with higher prevalence in males.
- The influence of sex on immunotherapy response in HCC is not well understood.
- NOTCH1 is an understudied oncogene in HCC with potential roles in sex-specific immunity.
Purpose of the Study:
- To investigate the role of NOTCH1 in sexually dimorphic antitumor immunity in HCC.
- To determine the impact of NOTCH1 on response to immunotherapy in HCC.
- To elucidate the mechanisms underlying sex differences in HCC immunity and immunotherapy response.
Main Methods:
- Utilized a novel HCC mouse model.
- Validated findings in human HCC patient data.
- Investigated immune cell populations (dendritic cells, T cells) and gene expression related to sex chromosomes.
Main Results:
- NOTCH1-driven tumors in males showed enhanced antitumor immunity mediated by dendritic and T cells.
- Females with NOTCH1-driven tumors exhibited immune evasion and immunotherapy resistance due to impaired dendritic cell (DC)-mediated CD8+ T cell priming.
- The observed sex differences were linked to sex chromosome genes, not sex hormones.
- Therapeutic CD40 agonism restored DC-CD8+ T-cell axis function in females.
Conclusions:
- NOTCH1 elicits sexually dimorphic antitumor immunity and immunotherapy response in HCC.
- A mechanism involving sex chromosome genes, not hormones, mediates these sex differences.
- Restoring the DC-CD8+ T-cell axis via CD40 agonism offers a potential strategy to improve immunotherapy outcomes in females with HCC.
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