Deciphering the potential role of PGRN in regulating CD8+ T cell antitumor immunity

Wenyu Zhang; Huan Qin; Guosheng Wang; Jing Zhang; Wenjuan He; Chunmei Feng; Huimin Wan; Feilong Wang; Zhongliang Guo

doi:10.1038/s41420-024-02001-7

Deciphering the potential role of PGRN in regulating CD8⁺ T cell antitumor immunity

Cell Death Discov. 2024 May 14;10(1):233. doi: 10.1038/s41420-024-02001-7.

Authors

Wenyu Zhang^#^{1

2}, Huan Qin^#^{1

2}, Guosheng Wang^{1

2}, Jing Zhang¹, Wenjuan He^{1

2}, Chunmei Feng^{1

2}, Huimin Wan^{1

2}, Feilong Wang³, Zhongliang Guo⁴

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
² Medical College, Tongji University, Shanghai, 200092, China.
³ Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. wang_feilong@tongji.edu.cn.
⁴ Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. drguozhl@163.com.

^# Contributed equally.

Abstract

A key factor contributing to resistance in immune checkpoint blockade (ICB) therapies is CD8⁺ T-cell tolerance in the tumor microenvironment (TME), partly resulting from upregulating coinhibitory receptors. Here, we describe the role of PGRN as a coinhibitory molecule that modulates the antitumor response of CD8⁺ T cells, thus presenting a novel immunosuppressive target for lung cancer. The in vivo subcutaneous transplanted lung cancer model showed that PGRN expression was elevated on CD8⁺ T cells that infiltrated transplanted lung cancers. Furthermore, PGRN deficiency was found to specifically encourage the infiltration of CD8⁺ T cells, enhance their proliferation, migration, and activation, and resist apoptosis, ultimately inhibiting tumor growth. This was achieved by PGRN knockout, increasing the production of T cell chemokine CCL3, which boosts the antitumor immune response induced by CD8⁺ T cells. Critically, the PD-L1 inhibitor exhibited a synergistic effect in enhancing the antitumor response in PGRN^-/- mice. In summary, our findings highlight the significance of PGRN as a novel target for boosting CD8⁺ T cells antitumor immunity and its potential to overcome the resistance in ICB therapy.

Abstract

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