Autophagic Flux Restoration of Senescent T Cells Improves Antitumor Activity of TCR-engineered T Cells

Overview

Journal Clin Transl Immunology

Specialty Allergy & Immunology

Date 2022 Oct 3

PMID 36188121

Authors

Chaoting Zhang

Yizhe Sun

Shance Li

Luyan Shen

Xia Teng

Yefei Xiao

Ping Zhou

Zheming Lu

Affiliations

Soon will be listed here.

Abstract

Objectives: Although adoptive cell therapy with T-cell receptor-engineered T cells (TCR-Ts) has mediated effective antitumor responses in several cancers, senescence of T cells could impair the therapeutic effect of TCR-Ts. Thus, it is essential to elucidate the characteristics of senescent TCR-Ts and how to subsequently improve their antitumor effect. Here, we focused on the influence of autophagy on TCR-Ts, since autophagy is tightly associated with the regulation of T-cell activation, proliferation and differentiation.

Methods: We first evaluated autophagy level of senescent TCR-Ts, and then the senescent TCR-Ts were expanded for 7 days with and without spermidine treatment, respectively. Furthermore, the proliferative potential, phenotypical characteristics and functionality of the propagated senescent TCR-Ts were analysed and after 7-day expansion.

Results: We found that autophagic flux of senescent TCR-T cells was significantly impaired. The restoration of autophagic flux via spermidine treatment reduced the expression of inhibitory immunoreceptors (PD-1, TIM-3 or LAG-3), enhanced proliferation and effector functions and subsequently demonstrated the superior and antitumor activity of TCR-Ts.

Conclusion: These data suggest that spermidine treatment presents an opportunity to improve the antitumor effect of TCR-Ts for the treatment of solid tumors.

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