Unraveling the Role of Lipid Metabolism in Regulating the Immune Checkpoints, and Developing

Strategies to Enhance the Adoptive Cell Transfer (ACT) Therapy

Bharti Aggarwal

Cancer progression often involves the evasion of immunosurveillance through intricate crosstalk between
cancer cells and stromal/immune counterparts via release of DAMPs, metabolites, chemokines, and cytokines.
While Adoptive T Cell Transfer (ACT) has emerged as a promising strategy in cancer immunotherapy, the
immunosuppressive tumor microenvironment (TME) of solid tumors, characterized by the expression of
immune checkpoint molecules like PD-L1, poses a formidable challenge to its effectiveness. Recent studies
have emphasized that altered metabolism in solid tumors is one of the key factors that contributes significantly
to the immunosuppression. In my talk, I will present our recent efforts in understanding the role of
sphingolipid metabolism in regulating the immunosuppression. Our findings revealed a correlation between
UDP-Glucosyltransferase (UGCG), a key enzyme in the sphingolipid pathway, expression and PD-L1
expression in different cancer types. Utilizing the FDA-approved UGCG inhibitor, Eliglustat, we
demonstrated that downregulation of UGCG decreases the PD-L1 expression in cancer and myeloid cells in
TME. We further showed that eliglustat enhanced the antitumor efficacy of B16 OVA-specific OT1 cells
against B16 OVA tumor models, and of HLA-mismatched PBMCs against human xenografts. Therefore, my
talk will shed light on the potential of combining ACT therapy with eliglustat to overcome
immunosuppression in solid tumors, offering a novel avenue for improving the outcomes of cancer
immunotherapy.