Abstract
BackgroundAlthough adoptive cell therapy with tumor infiltrating lymphocytes (TILs) has mediated effective antitumor responses in several cancers, dysfunction and exhaustion of TILs significantly impair the therapeutic effect of TILs. Thus, it is essential to elucidate the exhausted characteristics of TILs and improve the antitumor effect of TILs by reversing their exhaustion. Here, we focused on the influence of autophagy on TILs in terms of T-cell activation, proliferation, and differentiation in vitro and in vivo.MethodsWe first evaluated autophagy level of TILs and influence of spermidine treatment on autophagy levels of TILs. Furthermore, we assessed the proliferative potential, phenotypical characteristics, T cell receptor (TCR) repertoire and antitumor activity of TILs with and without spermidine treatment.ResultsWe found that autophagic flux of TILs, especially exhausted TILs that express inhibitory immunoreceptors and have impaired proliferative capacity and decreased production of cytotoxic effector molecules, was significantly impaired. The restoration of autophagic flux via spermidine treatment resulted in increased diversity of the TCR repertoire, reduced expression of inhibitory immunoreceptors (PD1, TIM3, or LAG3), enhanced proliferation and effector functions, which subsequently demonstrated the superior in vitro and in vivo antitumor activity of TILs. Our findings unveil that spermidine, as an autophagy inducer, reverses dysfunction and exhaustion of TILs and subsequently improves the antitumor activity of TILs.ConclusionsThese data suggest that spermidine treatment presents an opportunity to improve adoptive TIL therapy for the treatment of solid tumors.
Funder
Open Project funded by Key laboratory of Carcinogenesis and Translational Research,Ministry of Education/Beijing
Cooperation Fund of Beijing Cancer Hospital and Beijing Institute for Cancer Research; Clinical Medicine Plus X - Young Scholars Project
Natural Science Foundation of China
Peking University, the Fundamental Research Funds for the Central Universities
Capital’s Funds for Health Improvement and Research
National Natural Science Foundation of China
the Capital Health Research and Development of Special Funds
Beijing Municipal Administration of Hospital's Ascent Plan
Subject
Cancer Research,Pharmacology,Oncology,Molecular Medicine,Immunology,Immunology and Allergy
Cited by
2 articles.
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