CD137 Agonists Targeting CD137-Mediated Negative Regulation Show Enhanced Antitumor Efficacy in Lung Cancer

Ling Yi,Xu Cheng,Hongtao Zhang,Tao Wen,Xiaojue Wang,Bin Yang,Xin Jin,Zhuohong Yan,Jinghui Wang,Nanying Che,Zhidong Liu

doi:10.3389/fimmu.2022.771809

Ling Yi, Xu Cheng + Show 9 more

Open Access

https://doi.org/10.3389/fimmu.2022.771809

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Abstract

Negative immune regulation plays a notable role in tumor immunity. This study aimed to confirm that CD137 mediates negative immunoregulation as well as agonist activity in tumor immunity. Soluble CD137 (sCD137), a prominent splice variant of membrane-bound CD137 (mCD137), was identified, and its concentration in the blood of lung cancer patients was increased. The baseline concentration of sCD137 in the blood was negatively correlated with the efficacy of neoadjuvant immunochemotherapy in a pilot study. The percentage of CD137+ regulatory T cells (Tregs) in the blood of lung cancer patients was also increased, and further enriched at the tumor site; Foxp3, CTLA-4, IL-10, IL-35-Ebi3, sCD137 and costimulatory molecules expression were also higher, indicating increased immunosuppressive activity. A high percentage of CD137+ Tregs in the tumor was associated with worse OS outcomes among patients with high CD137+CD8+ T cell infiltration levels. Notably, targeting CD137+ Tregs using an engineered CD137 agonist with wild-type mouse IgG2a Fc clearly decreased the total Treg numbers and eliminated the tumor in the CT26 model and prolonged the survival rate of a Lewis lung carcinoma (LLC) model. These results indicated it may be possible to empower CD137 agonist with ability to abolish CD137-mediated negative regulation to enhance its antitumor efficacy.

Highlights

Checkpoint treatments, such as programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) blocking monoclonal antibodies, marked the beginning of the era of tumor immunotherapy
Considering that soluble CD137 (sCD137) negatively regulates CD137 signaling, we initially investigated the level of free sCD137 in the peripheral blood of 59 untreated lung cancer patients and 91 healthy donors
The present study focused on the negative regulation of tumor immunity mediated by CD137

Summary

Introduction

Checkpoint treatments, such as programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) blocking monoclonal antibodies (mAbs), marked the beginning of the era of tumor immunotherapy. PD-1/PD-L1 antibodies primarily regulate CD8+ T cell function and exhibit broad-spectrum therapeutic efficacy [1]. Tumors demonstrate primary and acquired resistance, and the benefit of such antibodies is generally low, with only 12.46% of all cancers and approximately 20% of the major types of lung cancer responding to the antibodies [2,3,4]. There has been noticeable progress in combining anti-PD-1/anti-CTLA-4 and anti-PD-L1/ anti-TIGIT, which have an objective response rate of 30-50% in advanced non-small-cell lung cancer (NSCLC) [6, 7]. It is essential to identify new targets for immunomodulation to broaden the application of immunotherapy to more patients, including those with lung cancer and other tumors [8]

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