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Combined disruption of T cell inflammatory regulators Regnase-1 and Roquin-1 enhances antitumor activity of engineered human T cells

David Mai,Omar Johnson,J. Reff,Ting-Jia Fan,J. Scholler,N. Sheppard,C. June

Published 2023 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance T cell therapies remain ineffective in solid tumor contexts, which induce hypofunction characterized by reduced cytotoxicity, proliferation, and cytokine function. Recent work has demonstrated that disrupting intrinsic inflammatory regulators, such as Regnase-1, which regulates the stability of inflammatory gene transcripts and induces hyperinflammation when disrupted in T cells, can increase antitumor responses. Here, we validate these observations in two clinical-stage immune receptor models and highlight that additional disruption of Roquin-1, a similar but nonredundant inflammatory regulator, in engineered T cells further improves solid tumor responses, more than disruption of either Regnase-1 or Roquin-1 alone. These results posit immune inflammatory regulators as a promising class of targets for multiplex disruption to develop more potent T cell therapies for solid tumors.

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