Overcoming immune suppression mediated by indoleamine 2,3-dioxygenase in adoptive cell therapies
Christopher G. May1,4*, Daniel J. Woodsworth2,3,4, Robert A. Holt4,5,6
1Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC
2Genome Science & Technology Program, University of British Columbia, Vancouver, BC
3MD/PhD Program, University of British Columbia, Vancouver, BC
4Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC
5Department of Medical Genetics, University of British Columbia, Vancouver, BC
6Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC
Adoptive T cell therapies, including CAR-T therapy, have shown tremendous promise in the treatment of certain hematological malignancies, but efficacy against solid tumours has been less pronounced. Reduced solid tumor efficacy is due to local immune suppression that is mediated, in part, by indoleamine 2,3-dioxygenase (IDO).
IDO is a tryptophan-degrading enzyme that results in the production of kynurenines (KYNs), a set of metabolites with potent anti-T cell activity. Specifically, tryptophan depletion and toxin accumulation in the tumour microenvironment promotes the differentiation of T Helper cells into regulatory T cells (Tregs) and directly induces CD8+ T-cell (CTL) anergy and apoptosis. The phenomenon of T Helper differentiation appears to be mediated by the aryl hydrocarbon receptor (AHR). We aim to further characterize this pathway of immunosuppression, and develop a strategy to overcome it in the context of CAR therapy.
We have evaluated the role of the AHR in the inhibition of CAR T-cell cytotoxicity using an in vitro, T Helper-independent system. We have additionally examined the relative contribution of the various KYNs to this phenomenon, and we are currently developing a cell-based secretion system to deliver a KYN-inhibiting enzyme to abrogate their toxicity. We aim to incorporate this strategy into existing CAR-T engineering paradigms in order to enhance their efficacy in vivo.
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