Orthogonal Gene Engineering Enables CD8+ T Cells to Control Tumors through a Novel PD-1+ TOX-indifferent Synthetic Effector State
Corria-Osorio, J.; Carmona, S. J.; Stefanidis, E.; Andreatta, M. J.; Muller, T.; Ortiz, Y.; Seijo, B.; Castro, W.; Jimenez-Luna, C.; Scarpellino, L.; Ronet, C.; Spill, A.; Lanitis, E.; Luther, S. A.; Romero, P.; Irving, M.; Coukos, G.
Show abstract
Adoptive immunotherapy offers opportunities to reprogram T cells and the tumor microenvironment. Orthogonal engineering of adoptively transferred T cells with an IL-2R{beta}{gamma}-binding IL-2 variant, PD1-decoy and IL-33 led to cell-autonomous T-cell expansion, T-cell engraftment and tumor control in immunocompetent hosts through reprogramming of both transferred and endogenous CD8+ cells. Tumor-infiltrating lymphocytes adopted a novel effector state characterized by TOX suppression and specific expression of multiple effector molecules, most prominently granzyme C. While the IL-2 variant promoted CD8+ T-cell stemness and persistence, and was associated with downregulation of TOX, the combination with IL-33 was necessary to trigger the novel polyfunctional effector state. Rational T-cell engineering without host lymphodepletion enables optimal reprogramming of adoptively transferred T cells as well as mobilization of endogenous immunity into new functional CD8+ states mediating tumor control.
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