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CD137 Agonists Targeting CD137-Mediated Negative Regulation Show Enhanced Antitumor Efficacy in Lung Cancer
Ling Yi1, Xin Jin1, Jinghui Wang2
1Department of Central Laboratory, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China.
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.
Insights
CD137 signaling can suppress anti-tumor immunity, particularly via regulatory T cells (Tregs). Targeting these CD137+ Tregs with specific agonists may enhance cancer immunotherapy effectiveness.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Negative immune regulation is crucial in tumor immunity.
- CD137 is implicated in both immune suppression and activation within tumors.
Purpose of the Study:
- To investigate the role of CD137 in mediating negative immunoregulation and agonist activity in tumor immunity.
- To explore the therapeutic potential of targeting CD137 in cancer.
Main Methods:
- Quantified soluble CD137 (sCD137) and CD137+ regulatory T cells (Tregs) in lung cancer patients.
- Analyzed correlations between CD137 markers, treatment efficacy, and patient outcomes.
- Utilized an engineered CD137 agonist to target CD137+ Tregs in preclinical tumor models (CT26 and Lewis lung carcinoma).
Main Results:
- Elevated sCD137 and CD137+ Tregs were observed in lung cancer patients, correlating with increased immunosuppression.
- High CD137+ Treg levels in tumors were linked to worse overall survival (OS) in patients with high CD137+CD8+ T cell infiltration.
- Targeting CD137+ Tregs with a CD137 agonist reduced Treg numbers, eradicated tumors in one model, and improved survival in another.
Conclusions:
- CD137 plays a dual role in tumor immunity, mediating both negative regulation and agonist activity.
- Soluble CD137 and CD137+ Tregs are potential biomarkers for immunotherapy efficacy and patient prognosis.
- Engineered CD137 agonists hold promise for enhancing anti-tumor efficacy by overcoming CD137-mediated immunosuppression.
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