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Theranostics 2024; 14(5):2167-2189. doi:10.7150/thno.92922 This issue Cite

Research Paper

Immunotherapeutic IL-6R and targeting the MCT-1/IL-6/CXCL7/PD-L1 circuit prevent relapse and metastasis of triple-negative breast cancer

Aushia Tanzih Al Haq1§, Pao-Pao Yang1§, Christopher Jin2, Jou-Ho Shih2, Li-Mei Chen1, Hong-Yu Tseng1, Yen-An Chen1, Yueh-Shan Weng1, Lu-Hai Wang3, Michael P. Snyder2, Hsin-Ling Hsu1✉

1. Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan.
2. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
3. Institute of Integrated Medicine and Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
§ These authors contributed equally to this work.

✉ Corresponding author: Hsin-Ling Hsu, Institute of Molecular and Genomic Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County, 35053, Taiwan. Phone: 886-37-206-166, ext. 35329; Fax: 886-37-586-459; E-mail: hsinling88edu.tw. More

Citation:
Haq ATA, Yang PP, Jin C, Shih JH, Chen LM, Tseng HY, Chen YA, Weng YS, Wang LH, Snyder MP, Hsu HL. Immunotherapeutic IL-6R and targeting the MCT-1/IL-6/CXCL7/PD-L1 circuit prevent relapse and metastasis of triple-negative breast cancer. Theranostics 2024; 14(5):2167-2189. doi:10.7150/thno.92922. https://www.thno.org/v14p2167.htm
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Abstract

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Rationale: Multiple copies in T-cell malignancy 1 (MCT-1) is a prognostic biomarker for aggressive breast cancers. Overexpressed MCT-1 stimulates the IL-6/IL-6R/gp130/STAT3 axis, which promotes epithelial-to-mesenchymal transition and cancer stemness. Because cancer stemness largely contributes to the tumor metastasis and recurrence, we aimed to identify whether the blockade of MCT-1 and IL-6R can render these effects and to understand the underlying mechanisms that govern the process.

Methods: We assessed primary tumor invasion, postsurgical local recurrence and distant metastasis in orthotopic syngeneic mice given the indicated immunotherapy and MCT-1 silencing (shMCT-1).

Results: We found that shMCT-1 suppresses the transcriptomes of the inflammatory response and metastatic signaling in TNBC cells and inhibits tumor recurrence, metastasis and mortality in xenograft mice. IL-6R immunotherapy and shMCT-1 combined further decreased intratumoral M2 macrophages and T regulatory cells (Tregs) and avoided postsurgical TNBC expansion. shMCT-1 also enhances IL-6R-based immunotherapy effectively in preventing postsurgical TNBC metastasis, recurrence and mortality. Anti-IL-6R improved helper T, cytotoxic T and natural killer (NK) cells in the lymphatic system and decreased Tregs in the recurrent and metastatic tumors. Combined IL-6R and PD-L1 immunotherapies abridged TNBC cell stemness and M2 macrophage activity to a greater extent than monotherapy. Sequential immunotherapy of PD-L1 and IL-6R demonstrated the best survival outcome and lowest postoperative recurrence and metastasis compared with synchronized therapy, particularly in the shMCT-1 context. Multiple positive feedforward loops of the MCT-1/IL-6/IL-6R/CXCL7/PD-L1 axis were identified in TNBC cells, which boosted metastatic niches and immunosuppressive microenvironments. Clinically, MCT-1high/PD-L1high/CXCL7high and CXCL7high/IL-6high/IL-6Rhigh expression patterns predict worse prognosis and poorer survival of breast cancer patients.

Conclusion: Systemic targeting the MCT-1/IL-6/IL-6R/CXCL7/PD-L1 interconnections enhances immune surveillance that inhibits the aggressiveness of TNBC.

Keywords: MCT-1, IL-6/IL-6R, CXCL7/CXCR2, PD-L1, Immunotherapy

Citation styles

APA
Haq, A.T.A., Yang, P.P., Jin, C., Shih, J.H., Chen, L.M., Tseng, H.Y., Chen, Y.A., Weng, Y.S., Wang, L.H., Snyder, M.P., Hsu, H.L. (2024). Immunotherapeutic IL-6R and targeting the MCT-1/IL-6/CXCL7/PD-L1 circuit prevent relapse and metastasis of triple-negative breast cancer. Theranostics, 14(5), 2167-2189. https://doi.org/10.7150/thno.92922.

ACS
Haq, A.T.A.; Yang, P.P.; Jin, C.; Shih, J.H.; Chen, L.M.; Tseng, H.Y.; Chen, Y.A.; Weng, Y.S.; Wang, L.H.; Snyder, M.P.; Hsu, H.L. Immunotherapeutic IL-6R and targeting the MCT-1/IL-6/CXCL7/PD-L1 circuit prevent relapse and metastasis of triple-negative breast cancer. Theranostics 2024, 14 (5), 2167-2189. DOI: 10.7150/thno.92922.

NLM
Haq ATA, Yang PP, Jin C, Shih JH, Chen LM, Tseng HY, Chen YA, Weng YS, Wang LH, Snyder MP, Hsu HL. Immunotherapeutic IL-6R and targeting the MCT-1/IL-6/CXCL7/PD-L1 circuit prevent relapse and metastasis of triple-negative breast cancer. Theranostics 2024; 14(5):2167-2189. doi:10.7150/thno.92922. https://www.thno.org/v14p2167.htm

CSE
Haq ATA, Yang PP, Jin C, Shih JH, Chen LM, Tseng HY, Chen YA, Weng YS, Wang LH, Snyder MP, Hsu HL. 2024. Immunotherapeutic IL-6R and targeting the MCT-1/IL-6/CXCL7/PD-L1 circuit prevent relapse and metastasis of triple-negative breast cancer. Theranostics. 14(5):2167-2189.

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