Disruption of the AHR signaling pathway enhances IL-17 production but negatively impacts proliferation of transgenic TCR and CAR T cells Kathryn A. Hooper1, Unja Martin1, Mark Pogson1, Joy Zhang1, Jordan Jarjour1, and Alexander Astrakhan1 1bluebird bio, Seattle, WA
Dysregulated tryptophan metabolism has been implicated in the pathogenesis of multiple cancers. Elevated activity of enzymes such as indoleamine 2,3 dioxygenase (IDO1) leads to enhanced degradation of tryptophan to immunosuppressive metabolites such as kynurenine (kyn). In T cells, kynurenine activates an immunosuppressive transcriptional program by binding to a ligand-activated transcription factor, the aryl hydrocarbon receptor (AHR). Subsequent AHR translocation to the nucleus drives a transcriptional cascade resulting in decreased cytokine production and T cell proliferation. Pharmacological modulation of tryptophan metabolism has produced promising clinical outcomes in several oncology areas. Additionally, previous studies have demonstrated decreased activity of chimeric antigen receptor (CAR) T cells against cell lines with high IDO1 activity, suggesting that blocking tryptophan metabolism may also enhance CAR T cell function. As an alternative strategy to pharmacological inhibition which acts on the tryptophan degradation pathway in tumor cells, we have used a megaTAL specific for the AHR gene to disrupt its function in T cells in an effort to render them resistant to kyn-mediated immunosuppression. We used two different model antigens to determine the functional consequence of AHR deletion on T cell function. T cells were transduced with lentiviral vectors encoding either a CAR specific for the Epidermal Growth Factor Receptor (EGFR) or a TCR specific for the cancer testis antigen NY-ESO-1. In short-term tumor co-culture assays, the AHR-edited EGFR CAR T and NY-ESO-1 cells exhibited similar cytolytic activity and cytokine production when compared to non-edited controls. Notably, AHR editing resulted in increased IL-17A cytokine production from both CAR and TCR T cells, consistent with a shift towards a Th17 phenotype. However, despite similar levels of viability, AHR-edited T cells demonstrated decreased proliferation and cytokine production following repeated rounds of antigen exposure. Combined, our findings confirm that AHR signaling negatively regulates IL-17 cytokine production and describe a previously unappreciated role for AHR in promoting T cell expansion.
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