Data from Genetic Regulation of Fate Decisions in Therapeutic T Cells to Enhance Tumor Protection and Memory Formation

• DOI: 10.1158/0008-5472.c.6506894.v1
• Publication Date: 2024-03-12T18:44:28Z
• Authors: Pedro Veliça; Mathias Zech; Sian Henson; Angelika Holler; Teresa Manzo; Rebecca Pike; Pedro Santos e Sousa; Lei Zhang; Bernhard Schiedlm...; Martin Pule; Hans Stauss; Ronjon Chakraverty

<div>Abstract<p>A key challenge in the field of T-cell immunotherapy for cancer is creating a suitable platform promoting differentiation effector cells while at same time enabling self-renewal needed long-term memory. Although transfer less differentiated memory T increases efficacy through greater expansion and persistence <i>in vivo</i>, capacity such to sustain functions within immunosuppressive tumor microenvironments may still be limiting. We have therefore directly compared impact versus therapeutic tumor-bearing mice by introducing molecular switches that regulate cell fate decisions via mTOR. Ectopic expression RAS homolog enriched brain (RHEB) increased mTORC1 signaling, promoted switch aerobic glycolysis, cells. By rapidly infiltrating tumors, RHEB-transduced significantly reduced emergence immunoedited escape variants. In contrast, proline-rich Akt substrate 40 kDa (PRAS40) inhibited mTORC1, quiescence, blocked infiltration. Fate mapping studies following transient PRAS40 demonstrated mTORC1<sup>low</sup> made no contribution initial control but instead survived become proficient generating recall immunity. Our data support design translational strategies heterogeneous immunity against cancer, with appropriate balance between self-renewal. Unlike pharmacologic inhibitors, genetic approach described here allows upregulation as well inhibition pathway highly selective without affecting systemic functions. <i>Cancer Res; 75(13); 2641–52. ©2015 AACR</i>.</p></div>