Juyeun Lee Laboratory

Research

Overview

Sex differences influence nearly every aspect of biology, from development, growth, and aging to metabolism and energy homeostasis. Despite this, the role of sex differences in disease, particularly cancer, has long been underappreciated.

Beyond reproductive cancers, many non-reproductive cancers show clear sex differences in incidence, therapeutic response, and survival. However, the mechanisms driving these differences are only beginning to be understood.

Biological sex shapes not only tumor cell behavior but also anti-tumor immune responses. The J. Lee Lab aims to define the mechanisms underlying sex-biased immunity and to develop therapeutic strategies tailored to the biological sex of patients. 

Impact of biological sex on immunometabolism and T cell function

Activation of naïve T cells requires a major metabolic shift to support increased energy demand and biosynthesis. This includes a transition from oxidative phosphorylation to glycolysis. In non-immune tissues such as skeletal and cardiac muscle, males and females differ in metabolic preferences—for example, female cells rely more on fatty acids and glutamine, whereas male cells preferentially use glucose.   

Within the tumor microenvironment (TME), tumor cells compete for nutrients and produce metabolites such as lactate, which impair T cell function. Maintaining metabolic fitness is therefore a key challenge in cancer immunotherapy. In addition, mitochondrial dysfunction is a hallmark of T cell exhaustion in chronic conditions such as cancer. Notably, mitochondrial function itself shows sex differences, with female mitochondria generally exhibiting enhanced resilience and reactive oxygen species (ROS) handling.   

Despite these observations, sex differences in immunometabolism remain poorly understood in T cells. Our lab addresses the following questions:

• Do sex differences in mitochondrial function emerge during T cell exhaustion?
• What mechanisms drive these differences?
• Do male and female T cells adapt differently to the metabolic constraints of the TME?
• Can targeting sex-specific metabolic pathways restore T cell function and improve anti-tumor immunity?   

Aging, sex hormones, and neuroinflammation in glioblastoma

Sex hormone levels change with aging, with men experiencing a more gradual decline compared to the abrupt changes of menopause in women. In men, testosterone levels decrease over time beginning in midlife, with a substantial proportion developing clinically low levels. Glioblastoma (GBM) is primarily a disease of aging, with a median age at diagnosis of 68–70 years. 

Aging is also associated with “immunoaging,” characterized by chronic, low-grade inflammation, including in the brain. This heightened neuroinflammatory state can promote tumor progression and worsen outcomes in GBM. However, how aging-associated changes in neuroinflammation influence anti-tumor immune responses remains poorly understood. In addition, the impact of age-related changes in sex hormones on the tumor microenvironment is largely unexplored.   

Our lab focuses on the intersection of aging, sex hormones, and neuroinflammation, addressing the following questions: 

• How does age-associated decline in sex hormones alter anti-tumor immune responses in GBM? 
• How does aging-associated neuroinflammation influence tumor progression and immune function? 
• Do aging and sex hormones interact to reshape the tumor microenvironment and response to immunotherapy? 

Selected Publications

NCBI: https://www.ncbi.nlm.nih.gov/myncbi/juyeun.lee.2/bibliography/public/ 

Selected Publications:    

• Lee J., Chung Y-M., Silver DJ., Hao Y., Harwood DSL., Early A., Serapiglia AM., Curtin L., Benedetti JR., Ballard CAP., Lapsley K., Alvarez-Vazquez., Goldberg J., Li C., Kaur S., Neal R., Wang SZ., Kay KE., Volovetz J., Hong ES., Fodor R., Jarmular J., Nicosia M., Rubin JB., Swanson KR., Ostrom QT., Panicker N., Kristensen BW., Berens M., Sharifi N., Lathia JD., “Androgen loss accelerates brain tumor growth via HPA axis activation”. Nature (2026). doi: 10.1038/s41586-026-10451-5 
• Xiao T.*, Lee J.*, Gauntner TD., Velegraki M., Lathia JD., Li Z., Perspective: “Mechanisms and therapeutic implications of sex bias in immuno-oncology”. Nature Reviews Cancer (2024). doi: 10.1038/s41568-024-00680-z. PMID: 38589557 (*denotes co-first author)  Kay KE., Lee J., Hong ES., Beilis J., Dayal S., Wesley E., Mitchell S., Wang SZ, Silver DJ., Volovetz J., Johnson S., McGraw M., Grabowski MM., Lu T., Freytag L., Narayana V., Freytag S., Best S., Whittle J., Wang Z, Reizes O., Yu J., Hazen S., Brown JM., Bayik D., Lathia JD., “Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition”. Journal of Clinical Investigation (2024). doi: 10.1172/JCI177824. PMID: 39561012 PMCID: PMC11735101 
• Lee J., Park N., Nicosia M., Park JY., Pruett SB., Seo KS., “Stimulation strength determined by superantigen dose controls subcellular localization of FOXP3 isoforms and suppressive function of CD4+CD25+FOXP3+ T cells”. Journal of Immunology (2024). doi: 10.4049/jimmunol.2300019. PMID: 38108423, PMCID: PMC10784726 
• Kim D., Kim G., Yu R., Lee J., Kim S., Gleason MR., Qiu K., Montauti E., Wang LL., Fang D., Choi J., Chandel N., Weinberg S., Min B., “Inhibitory co-receptor LAG3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming”. Immunity (2024). doi: 10.1016/j.immuni.2024.08.008. PMID: 39236718 
• Lee J., Nicosia M., Hong ES., Silver DJ., Li C., Bayik D., Watson DC., Lauko A., Kay KE., Wang SZ., Johnson S., McGraw M., Grabowski MM., Kish DD., Desai AB., Goodman WA., Cameron SJ., Okada H., Valujskikh A., Fairchild RL., Ahluwalia MS., Lathia JD., “Sex-biased T cell exhaustion drives differential immune responses in glioblastoma”. Cancer Discovery (2023). doi:10.1158/2159-8290.CD-22-0869. PMID: 37378557 PMCID: PMC10481130  
• Bayik D., Bartels C., Lovrenert K., Watson DC., Zhang D., Kay K., Lee J., Lauko A., Silver DJ, Mohammadi A., Veglia F., Yi Fan, Vogelbaum MA., Scacheri P., Lathia JD., “Distinct cell adhesion signature defines glioblastoma myeloid-derived suppressor cell subsets”. Cancer Research (2022). doi: 10.1158/0008-5472.CAN-21-3840. PMID: 36126163 PMCID: PMC9664137 
• Kim D.*, Nguyen QT.*, Lee J., Lee S., Janocha Al., Kim S., Le HT., Dvorina N., Weiss K., Asosingh K., Erzurum SC., Baldwin WM., Lee J-S., Min B., “Anti-inflammatory roles of glucocorticoids are directed by Foxp3+regulatory T cells via a novel miR-342-dependent mechanism”. Immunity (2020). doi: 10.1016/j.immuni.2020.07.002. PMID: 32707034 PMCID: PMC7793548 (*denotes co-first author) 
• Kim D., Le HT., Nguyen QT., Kim S., Lee J., Min B., “IL-27 attenuates autoimmune neuroinflammation via regulatory T cell/LAG3-dependent but IL-10-independent mechanisms in vivo”. Journal of Immunology (2019). doi: 10.4049/jimmunol.1800898. PMID: 30700587 PMCID: PMC6401226 
• Lee J., Park N., Park JY., Kaplan BLF., Pruett SB., Park JW., Seo KS., “Induction of immunosuppressive CD8+CD25+FOXP3+ regulatory T cells by a suboptimal stimulation by staphylococcal enterotoxin C1”. Journal of Immunology (2018). doi: 10.4049/jimmunol.1602109. PMID: 29237775 PMCID: PMC5757107