4-1BB stimulation with concomitant inactivation of adenosine A2B receptors enhances CD8<sup>+</sup> T cell antitumor response

Jihae Ahn; Ping Xie; Siqi Chen; Guilan Shi; Jie Fan; Minghui Zhang; Hui Tang; Amanda R. Zuckerman; Deyu Fang; Yong Wan; Timothy M. Kuzel; Yi Zhang; Bin Zhang

doi:10.1172/JCI190841

4-1BB stimulation with concomitant inactivation of adenosine A2B receptors enhances CD8⁺ T cell antitumor response

Published April 3, 2025 - More info

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Abstract

Activating the immune co-stimulatory receptor 4-1BB (CD137) with agonist antibody binding and crosslinking-inducing agents that elicit 4-1BB intracellular signaling potentiates the antitumor responses of CD8 T cells. However, the underlying in-depth mechanisms remain to be defined. Here, we show that agonistic 4-1BB treatment of activated CD8⁺ T cells under continuous antigenic stimulation are more metabolically vulnerable to redox perturbation by ablation of intracellular glutathione (GSH) and glutathione peroxidase 4 (GPX4) inhibition. Further, genetic deletion of adenosine A2B receptor (A2BR) induces superior survival and expansion advantage of competent CD8⁺ T cells with agonistic 4-1BB costimulation, leading to more effective antitumor efficacy of adoptive cell therapy (ACT). Mechanistically, A2BR deletion helps sustain the increased energy and biosynthetic requirements through the GSH-GPX4 axis upon 4-1BB costimulation. A2BR deletion in combination with agonistic 4-1BB costimulation displays a greater ability to promote antitumor CD8⁺ effector T cell survival and expansion while mitigating T cell exhaustion. Thus, the A2BR pathway plays an important role in metabolic reprogramming with potentiation of the GSH-GPX4 cascade upon agonistic 4-1BB costimulation that allows the fine-tuning of the antitumor responses of CD8⁺ T cells.

4-1BB stimulation with concomitant inactivation of adenosine A2B receptors enhances CD8⁺ T cell antitumor response

Jihae Ahn,¹ Ping Xie,¹ Siqi Chen,¹ Guilan Shi,¹ Jie Fan,¹ Minghui Zhang,¹ Hui Tang,¹ Amanda R. Zuckerman,¹ Deyu Fang,² Yong Wan,³ Timothy M. Kuzel,¹ Yi Zhang,⁴ and Bin Zhang¹

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4-1BB stimulation with concomitant inactivation of adenosine A2B receptors enhances CD8+ T cell antitumor response

Jihae Ahn,1 Ping Xie,1 Siqi Chen,1 Guilan Shi,1 Jie Fan,1 Minghui Zhang,1 Hui Tang,1 Amanda R. Zuckerman,1 Deyu Fang,2 Yong Wan,3 Timothy M. Kuzel,1 Yi Zhang,4 and Bin Zhang1

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4-1BB stimulation with concomitant inactivation of adenosine A2B receptors enhances CD8⁺ T cell antitumor response

Jihae Ahn,¹ Ping Xie,¹ Siqi Chen,¹ Guilan Shi,¹ Jie Fan,¹ Minghui Zhang,¹ Hui Tang,¹ Amanda R. Zuckerman,¹ Deyu Fang,² Yong Wan,³ Timothy M. Kuzel,¹ Yi Zhang,⁴ and Bin Zhang¹