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Zeaxanthin augments CD8+ effector T cell function by enhancing TCR stimulation

ABSTRACT: The detailed mechanisms underlying regulatory significance of dietary components in modulating anti-tumor immunity remain largely unknown. Here, we applied a co-culture screen approach using a blood nutrient compound library to identify zeaxanthin, a dietary carotenoid pigment found in many fruits and vegetables that is important for eye health, as an immunomodulator that enhances cytotoxicity of CD8+ T cells towards tumor cells. Oral zeaxanthin, but not lutein, a carotenoid with similar structure, enhances anti-tumor immunity in vivo. Integrated multi-omics mechanistic studies reveal that zeaxanthin directly promotes T-cell receptor (TCR) stimulation on CD8+ T cell surface, leading to improved intracellular TCR signaling for effector T cell function. Hence, zeaxanthin treatment augments effectiveness of immune checkpoint inhibitor in vivo and human TCR-engineered CD8+ T cells to induce cell death in co-cultured tumor cells. Our findings uncover a previously unknown immunoregulatory function of zeaxanthin, which has translational potential as a dietary element in immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE282686 | GEO | 2025/08/22

REPOSITORIES: GEO

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Project description:Objective: The dietary xanthophylls, lutein and zeaxanthin, accumulate in primate brain and may be beneficial for cognition. Brain xanthophyll content varies greatly among individuals and genetic factors are likely to be significant contributors. Subspecies of rhesus macaques originating from different geographic locations differ genetically, but the effect of origin on gene expression and carotenoid status has not been determined. The study objective was to determine whether xanthophyll status and expression of carotenoid-related genes, as well as genes with known variants between subspecies, differ between the brains of adult rhesus monkeys of Indian and Chinese origin. Methods: Next generation RNA sequencing was used to determine differentially expressed carotenoid-related genes and genes with known variants among rhesus monkey subspecies in the prefrontal cortex, cerebellum, and striatum of Indian-origin monkeys (n=3) versus Chinese-origin monkeys (n=3). Serum and brain xanthophylls were determined using HPLC. FastQC was performed on raw sequenced reads to determine the quality of each read. Reads were mapped to the Rhesus Macaque reference genome and differences in gene expression (FPKM) were determined using TopHat and Cuffdiff, respectively. Findings from RNAseq were validated using RT-PCR. Results: Indian-origin monkeys had higher xanthophyll levels in brain tissue compared to Chinese-origin monkeys despite consuming similar amounts of dietary carotenoids. In a region-specific manner, 4 genes related to carotenoid and fatty acid metabolism (BCO2, RPE65, ELOVL4, FADS2) and 4 genes involved in the immune response (CD4, CD74, CXCL12 LTBR) were differentially expressed between Indian- and Chinese-origin monkeys. Expression of all four genes involved in carotenoid and fatty acid metabolism were correlated with brain xanthophyll concentration in a region-specific manner. Conclusions: These results indicate that origin is related to differences in both gene expression and xanthophyll content in the brain. Findings from this study may have important implications regarding genetic diversity, lutein status, and cognition in primates.

Project description:Background: Anti-tumor immunity is highly heterogeneous between individuals; however, underlying mechanisms remain elusive, despite their potential to improve personalized cancer immunotherapy. Head and neck squamous cell carcinomas (HNSCCs) vary significantly in immune infiltration and therapeutic responses between patients, demanding a mouse model with appropriate heterogeneity to investigate mechanistic differences. Methods: We developed a unique HNSCC mouse model to investigate underlying mechanisms of heterogeneous anti-tumor immunity. This model system may provide a better control for tumor-intrinsic and host-genetic variables, thereby uncovering the contribution of the adaptive immunity to tumor eradication. We employed single-cell T-cell receptor (TCR) sequencing coupled with single-cell RNA sequencing to identify the difference in TCR repertoire of CD8 tumor infiltrating lymphocytes (TILs) and the unique activation states linked with different TCR clonotypes. Results: We discovered that genetically identical wild-type recipient mice responded heterogeneously to the same SCC tumors orthotopically transplanted into the buccal mucosa. While tumors initially grew in 100% of recipients and most developed aggressive tumors, ~25% of recipients reproducibly eradicated tumors without intervention. Heterogeneous anti-tumor responses were dependent on CD8 T cells. Consistently, CD8 TILs in regressing tumors were significantly increased and more activated. Single-cell TCR-sequencing revealed that CD8 TILs from both growing and regressing tumors displayed evidence of clonal expansion compared with splenic controls. However, top TCR clonotypes and TCR specificity groups appear to be mutually exclusive between regressing and growing TILs. Furthermore, many TCRa/TCRb sequences only occur in one recipient. By coupling single-cell transcriptomic analysis with unique TCR clonotypes, we found that top TCR clonotypes clustered in distinct activation states in regressing vs. growing TILs. Intriguingly, the few TCR clonotypes shared between regressors and progressors differed greatly in their activation states, suggesting a more dominant influence from tumor microenvironment than TCR itself on T cell activation status. Conclusions: We reveal that intrinsic differences in the TCR repertoire of TILs and their different transcriptional trajectories may underlie the heterogeneous anti-tumor immune responses in different hosts. We suggest that anti-tumor immune responses are highly individualized and different hosts employ different TCR specificities against the same tumors, which may have important implications for developing personalized cancer immunotherapy.

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Zeaxanthin augments CD8+ effector T cell function by enhancing TCR stimulation

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