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ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance
Jacob J Orme1, Khalid A Jazieh2,3, Tiancheng Xie2
1Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
Abstract:
ADAM10 and ADAM17 expression and soluble PD-L1 (sPD-L1) predict poor prognosis in many malignancies, including in patients treated with PD-(L)1 inhibitors. The mechanism of soluble PD-L1 production and its effects are unknown. Here we uncover a novel mechanism of ADAM10- and ADAM17-mediated resistance to PD-(L)1 inhibitors. ADAM10 and ADAM17 cleave PD-L1 from the surface of malignant cells and extracellular vesicles. This cleavage produces an active sPD-L1 fragment that induces apoptosis in CD8 + T cells and compromises the killing of tumor cells by CD8 + T cells. Reduced tumor site PD-L1 protein-to-mRNA ratios predict poor outcomes and are correlated with elevated ADAM10 and ADAM17 expression in multiple cancers. These results may explain the discordance between PD-L1 immunohistochemistry and PD-(L)1 inhibitor response. Thus, including ADAM10 and ADAM17 tissue staining may improve therapy selection. Furthermore, treatment with an ADAM10/ADAM17 inhibitor may abrogate PD-(L)1 inhibitor resistance and improve clinical responses to PD-(L)1 immunotherapy.
Insights
ADAM10 and ADAM17 enzymes release soluble PD-L1, hindering anti-cancer immunotherapy. Inhibiting these enzymes may overcome resistance and improve treatment responses in various cancers.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- ADAM10 and ADAM17 expression, along with soluble PD-L1 (sPD-L1), are linked to poor prognosis in many cancers.
- The mechanisms behind sPD-L1 production and its functional impact remain largely unknown.
- This is particularly relevant for patients undergoing PD-(L)1 inhibitor therapy.
Purpose of the Study:
- To investigate the novel mechanism of ADAM10- and ADAM17-mediated resistance to PD-(L)1 inhibitors.
- To elucidate the role of ADAM10 and ADAM17 in the production of soluble PD-L1.
- To explore the therapeutic potential of targeting ADAM10/ADAM17 in overcoming immunotherapy resistance.
Main Methods:
- Analysis of ADAM10 and ADAM17 expression in relation to PD-L1 levels and patient outcomes.
- Investigation of ADAM10 and ADAM17 enzymatic activity in cleaving PD-L1 from cell surfaces and extracellular vesicles.
- Assessment of the impact of sPD-L1 on CD8+ T cell apoptosis and anti-tumor activity.
- Correlation of tumor PD-L1 protein-to-mRNA ratios with ADAM10/ADAM17 expression and clinical data.
Main Results:
- ADAM10 and ADAM17 were found to cleave PD-L1 from malignant cells and extracellular vesicles, generating active sPD-L1.
- The produced sPD-L1 was shown to induce apoptosis in CD8+ T cells and impair their tumor-killing capacity.
- Reduced tumor PD-L1 protein-to-mRNA ratios, indicative of poor prognosis, correlated with elevated ADAM10 and ADAM17 expression across multiple cancer types.
- These findings provide a potential explanation for the discrepancy between PD-L1 immunohistochemistry and response to PD-(L)1 inhibitors.
Conclusions:
- ADAM10 and ADAM17 mediate resistance to PD-(L)1 inhibitors through the generation of sPD-L1.
- Tissue staining for ADAM10 and ADAM17 may enhance the selection of patients for immunotherapy.
- Targeting ADAM10/ADAM17 with inhibitors presents a promising strategy to overcome PD-(L)1 inhibitor resistance and improve immunotherapy efficacy.
