Immunoengineering cellobiose as a fuel source for T cells

摘要

Abstract Glucose levels are low in the microenvironment of solid tumors due to the voracious nature of tumor metabolism, impeding the function of tumor-infiltrating T cells that might otherwise control tumor growth. T cells require glucose for energetics, cytokine production, proliferation, and cytotoxicity. Infusing additional glucose into patients is not a viable solution as it would feed only the tumor and further starve T cells. Adoptive cell therapies (CAR-T cells) often fail in solid tumors because of this metabolic hurdle created by tumors. Cellobiose, a polymer of glucose found abundantly in plant matter in the form of cellulose, has the potential to serve as a carbon and energy source. However, mammalian cells cannot catabolize cellobiose. Our preliminary data show that engineering two proteins into T cells allows them to make use of cellobiose. Thus, we already have a working system set up to engineer T cells to have an exclusive source of glucose to fight tumors. We showed this glucose source is completely inaccessible to tumors. Our long-term goal is to translate this capability to T cells that are engineered for cancer immunotherapy (e.g., CAR-T cells). Our team includes T-cell immunologists at UCLA assisted by expert colleagues in immune metabolism and cancer immunotherapies. In this R21 proposal, we will in Aim 1, characterize as cellobiose is hydrolyzed to glucose, and trace its carbons into various metabolic and biosynthetic pathways and provide energy. We test the capacity of cells to use cellobiose-derived glucose through state-of-the-art metabolomics in 293 cell lines and primary T cells. In Aim 2, we test toxicity and pharmacokinetics to prepare for melanoma experiments in mice. We test in a proof-of-concept experiment the ability of T cells to fight mouse melanomas, using transduced pmel TCR transgenics and CAR-T cells that target melanoma. By adding cellobiose metabolism to engineered T cells, we offer a new fuel source and a synergistic approach that significantly potentiates cancer immunotherapies.