The effectiveness of cancer immunotherapy with checkpoint inhibitors or T-cell therapies often is limited by the presence of immunosuppressive factors in the tumor microenvironment. Kynurenine, a metabolite of the amino acid tryptophan, is one such factor. Clinical data have suggested a correlation between this metabolite and the aggressiveness of certain tumors. The presence of high levels of kynurenine relative to tryptophan levels, for example, has been associated with worse overall survival in people with melanoma and renal cell cancer who are being treated with anti-PD1 checkpoint blockade. Furthermore, melanoma cell lines that produce kynurenine induce the expression of exhaustion markers on CD4+ T cells.
In this project, a team led by David Hockenbery of the Fred Hutchinson Cancer Research Center is equipping tumor-infiltrating lymphocytes (TILs) with enzymatic machinery to convert kynurenine into nutrients that will support the ability of these T cells to attack tumor cells. Their novel strategy aims to transform kynurenine from a negative regulator of T cell function into a positive stimulus of antitumor immunity. Not only will anti-tumor T cells become invigorated rather than suppressed by the uptake of kynurenine, but also immunosuppressive T cells, or Tregs, will be inhibited by the depletion of kynurenine in the TME. The team also aims to further modulate the kynurenine pathway by increasing the retention of tryptophan in T cells. T cells require tryptophan for their antitumor function and proliferation, and such modulation could lead to selective fueling of T cells over tumor cells. The goal of these studies, which are being conducted in pre-clinical models of melanoma, is to determine whether specific metabolic reprogramming of T cells to avoid kynurenine-based immunosuppression can augment the anti-tumor immune response and potentially expand the list of tumors susceptible to these immunotherapies.