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

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. Overall design: RNA seq profiling of mouse primary CD8+ T cells treated with Zeaxanthin, Lutein, and DMSO. (n=3)