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

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

doi:10.3389/fimmu.2022.771809

Cited by 3 publications

(5 citation statements)

References 53 publications

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“…2) Elimination of Tregs was observed in the doublet group, similar to the aCD137 group, which was also reported by Freeman et al. ( 27 ) and our previous study ( 11 ). The reduction of Tregs was probably because of the antibody-mediated cell-dependent phagocytosis (ADCP) of Tregs, mediated by the activation of macrophages by IgG-Fc ( 28 – 30 ).…”

Section: Discussionsupporting

confidence: 87%

PCSK9 regulates the efficacy of immune checkpoint therapy in lung cancer

Gao

Jiang

et al. 2023

Front. Immunol.

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) secreted by tumors was reported as a deleterious factor that led to the reduction of lymphocyte infiltration and the poorer efficacy of ICIs in vivo. This study aimed to explore whether PCSK9 expression in tumor tissue could predict the response of advanced non-small cell lung cancer (NSCLC) to anti-PD-1 immunotherapy and the synergistic antitumor effect of the combination of the PCSK9 inhibitor with the anti-CD137 agonist. One hundred fifteen advanced NSCLC patients who received anti-PD-1 immunotherapy were retrospectively studied with PCSK9 expression in baseline NSCLC tissues detected by immunohistochemistry (IHC). The mPFS of the PCSK9lo group was significantly longer than that of the PCSK9hi group [8.1 vs. 3.6 months, hazard ratio (HR): 3.450; 95% confidence interval (CI), 2.166-5.496]. A higher objective response rate (ORR) and a higher disease control rate (DCR) were observed in the PCSK9lo group than in the PCSK9hi group (54.4% vs. 34.5%, 94.7% vs. 65.5%). Reduction and marginal distribution of CD8+ T cells were observed in PCSK9hi NSCLC tissues. Tumor growth was retarded by the PCSK9 inhibitor and the anti-CD137 agonist alone in the Lewis lung carcinoma (LLC) mice model and further retarded by the PCSK9 inhibitor in combination with the CD137 agonist with long-term survival of the host mice with noticeable increases of CD8+ and GzmB+ CD8+ T cells and reduction of Tregs. Together, these results suggested that high PCSK9 expression in baseline tumor tissue was a deleterious factor for the efficacy of anti-PD-1 immunotherapy in advanced NSCLC patients. The PCSK9 inhibitor in combination with the anti-CD137 agonist could not only enhance the recruitment of CD8+ and GzmB+ CD8+ T cells but also deplete Tregs, which may be a novel therapeutic strategy for future research and clinical practice.

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Section: Discussionsupporting

confidence: 87%

PCSK9 regulates the efficacy of immune checkpoint therapy in lung cancer

Gao

Jiang

et al. 2023

Front. Immunol.

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“…Interestingly, Tregs are also the main cellular source of soluble CD137. Single-cell sequencing analysis suggests that CD137 + and CTLA-4 + expression on Tregs is related to lung cancer antigens [ 46 ]. Unfortunately, in our study we only had access to serum samples, so we were not able to explore the association of Tregs in this context.…”

Section: Discussionmentioning

confidence: 99%

Sleep apnoea increases biomarkers of immune evasion, lymphangiogenesis and tumour cell aggressiveness in high-risk patients and those with established lung cancer

Cubillos-Zapata,

Troncoso-Acevedo,

Díaz-García

et al. 2024

ERJ Open Res

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Intermittent hypoxemia and obstructive sleep apnoea (OSA) have been linked to lung cancer through as yet unidentified pathophysiological mechanisms. This study evaluates the effect of OSA on serum levels of biomarkers of immunosurveillance, lymphangiogenesis, and intrinsic tumour cell aggressiveness in high-risk individuals screened for lung cancer and patients with established lung cancer.Serum samples from individuals participating in a lung cancer screening cohort (SAILS study) or with newly diagnosed lung cancer (SAIL study) were analysed. All patients underwent home sleep apnoea testing (HSAT). Soluble levels of program death-1 (PD-1), program death ligand-1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA4), midkine (MDK), paraspeckle protein-1 (PSPC-1), transforming growth factor-β1 (TGF-ß1), SMAD3, matrix metalloproteinase-2 (MMP2) and co-stimulus receptor of the tumour necrosis factor family of receptors (CD137) were determined by EIA.The presence of moderate-severe OSA was associated with increased levels of PSPC-1, MDK, PD-L1 and PD-1 in screened individuals, and with higher values of PSPC-1, TGF-ß1, PD-L1 and PD-1 in patients with established lung cancer. The findings correlated with nocturnal intermittent hypoxemia indices.In conclusion, moderate to severe OSA is associated with increased expression of serum biomarkers of immune evasion, lymphangiogenesis and tumour cell aggressiveness in high-risk individuals screened for lung cancer and those with established disease.

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“…A previously described ELISA [31] was used to detect sCD137 in plasma and pleural effusion samples. Briefly, an antihuman CD137 mAb (2 μg/mL, h41BB-M127, BD Pharmingen) was used to coat ELISA plates, and undiluted plasma or pleural fluid samples were added after the plates were blocked and incubated for 2 h at room temperature (RT).…”

Section: Elisamentioning

confidence: 99%

“…Low levels of sCD137 can be measured in the peripheral blood of healthy people. Elevated levels of sCD137 have been measured in the sera or plasma of autoimmune patients, including those with rheumatoid arthritis, systemic sclerosis, MS and systemic lupus erythematosus [11,[16][17][18][19][20]; inflammation-related patients, including those with acute coronary syndromes and acute pancreatitis [21][22][23][24]; and tumour patients, including those with haematologic malignancies, uveal melanoma, hepatocellular carcinoma, pancreatic cancer and lung cancer [25][26][27][28][29][30][31]. sCD137 interferes with the interaction between CD137L and membranebound CD137 (mCD137) and inhibits the activities of the CD137 receptor/ligand systems and therapeutic CD137 agonists.…”

Section: Introductionmentioning

confidence: 99%

“…sCD137 interferes with the interaction between CD137L and membranebound CD137 (mCD137) and inhibits the activities of the CD137 receptor/ligand systems and therapeutic CD137 agonists. Therefore, elevated levels of sCD137 are beneficial for tumour cell survival and predict poor prognosis and no response to treatment in patients with tumours [13,25,[28][29][30][31]. In inflammatory states, sCD137 levels are positively correlated with disease severity, and dynamic changes in sCD137 can reflect patient disease activity and stability status [16,19,20].…”

Section: Introductionmentioning

confidence: 99%

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The levels of soluble CD137 are increased in tuberculosis patients and associated with disease severity and prognosis

Yi,

Yan,

Wei

et al. 2024

Eur J Immunol

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Tuberculosis (TB) was the leading cause of death from a single infectious agent before the coronavirus pandemic. Therefore, it is important to search for severity biomarkers and devise appropriate therapies. A total of 139 pulmonary TB (PTB) patients and 80 healthy controls (HCs) were recruited for plasma soluble CD137 (sCD137) detection through ELISA. Moreover, pleural effusion sCD137 levels were measured in 85 TB patients and 36 untreated lung cancer patients. The plasma cytokine levels in 64 patients with PTB and blood immune cell subpopulations in 68 patients with PTB were analysed via flow cytometry. Blood sCD137 levels were higher in PTB patients (p = 0.012) and correlated with disease severity (p = 0.0056). The level of sCD137 in tuberculous pleurisy effusion (TPE) was markedly higher than that in malignant pleurisy effusion (p = 0.018). Several blood cytokines, such as IL‐6 (p = 0.0147), IL‐8 (p = 0.0477), IP‐10 (p ≤ 0.0001) and MCP‐1 (p = 0.0057), and some laboratory indices were significantly elevated in severe PTB (SE) patients, but the percentages of total lymphocytes (p = 0.002) and cytotoxic T cells (p = 0.036) were significantly lower in SE patients than in non‐SE patients. In addition, the sCD137 level was negatively correlated with the percentage of total lymphocytes (p = 0.0008) and cytotoxic T cells (p = 0.0021), and PTB patients with higher plasma sCD137 levels had significantly shorter survival times (p = 0.0041). An increase in sCD137 is a potential biomarker for severe TB and indicates a poor prognosis.

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

Cited by 3 publications

References 53 publications

PCSK9 regulates the efficacy of immune checkpoint therapy in lung cancer

PCSK9 regulates the efficacy of immune checkpoint therapy in lung cancer

Sleep apnoea increases biomarkers of immune evasion, lymphangiogenesis and tumour cell aggressiveness in high-risk patients and those with established lung cancer

The levels of soluble CD137 are increased in tuberculosis patients and associated with disease severity and prognosis

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