Delighted to share our paper, biorxiv.org/content/10.110… . Huge thanks to @CoukosGeorge for the opportunity as well as all our collaborators, @carmonation. A summary of our main findings:
Orthogonal combinatorial T-cell engineering overcomes homeostatic barriers to engraftment, reprograms TILs as well as the tumor microenvironment and mediates solid tumor regression in the absence of preconditioning or systemic cytokine support @CoukosGeorge, @carmonation
As a proof of principle of orthogonal T-cell engineering, here we successfully combined two main secreted components: an IL-2 variant binding to b/g but not IL-2Ra (promote T-cell stemness), together with the pro-inflammatory alarmin IL-33.
Antitumor efficacy of orthogonal T-cell engineering is mediated by a novel synthetic effector cell state with direct antitumor potential. This novel state exhibited exhaustion markers (PD-1, TIM3) but not TOX, the central transcription factor implicated in exhaustion.
Despite expressing PD-1 and TIM3, TILs in the synthetic effector state were not constrained by these canonical inhibitory checkpoints; blockade of PD-1 and/or TIM3, or addition of a PD-1 decoy gene engineering module in the cells, was functionally inconsequential.
Moreover, the novel synthetic effector state diverges from the transitory effector-like exhausted state (CX3CR1+TIM3+PD-1+) and PD1neg short-lived effector cells (SLEC)
We also found that orthogonally engineering drive high- as well as low-affinity tumor-specific endogenous CD8+ TILs PD-1+CD8+ TILs away from canonical PD-1+TOX+ exhaustion, transcriptionally reprogramming them to adopt synthetic-like polyfunctional effector states.
Orthogonally engineering ACT also reprograms PD-1+ TCF1+ precursor-like TILs within the tumor microenvironment
Overall our work unlocks the novel opportunity of generating synthetic CD8+ T-cell states endowed with the ability to control advanced, poorly immunogenic, and PD-1 blockade resistant solid tumors by combinatorial engineering of novel cytokines.
The therapeutic manipulation of TOX has been proposed as a promising strategy to abrogate T-cell exhaustion in the context of cancer.
In this study, we show a novel approach to reach synthetic cell states in which TOX is suppressed transcriptionally without genome editing or knockdown, in both adoptively transferred as well as endogenous CD8+ T cells
Such decoupling of T-cell activation/differentiation from TOX in the presence of exhaustion markers, in both endogenous and exogenous CD8+ T-cell compartments, is an important and unexpected finding opening new directions in our thinking of synthetic reprogramming of T cells.
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