Abstract A022: Immunotherapy of IL-6R Prevents Relapse and Metastasis of Triple-Negative Breast Cancer

Abstract

Abstract Multiple Copies in T-cell Malignancy-1 (MCT-1 or MCTS1) is a prognostic biomarker for aggressive breast cancers. Overexpressed MCT-1 stimulates the IL-6/IL-6R/gp130/STAT3 axis, promoting epithelial-to-mesenchymal transition, cancer cell stemness and tumor progression. To study the mechanism underlying TNBC immunity and aggressiveness, TNBC cell lines with different MCT-1 expression levels were evaluated. Primary tumor invasion and postsurgical local recurrence and distant metastasis were assessed in orthotopic syngeneic mice given indicated immunotherapy and/or MCT-1 silencing (shMCT-1). We found that shMCT-1 suppresses the transcriptome of inflammatory response and metastatic signaling in TNBC cells and inhibits TNBC progression, metastasis and mortality in xenograft mice. Combined IL-6R immunotherapy and shMCT-1 effect further decreased intratumoral M2 macrophages and T regulatory cells (Tregs) and avoided postsurgical TNBC expansion. Multiple positive feedback loops of the MCT-1/IL-6/IL-6R/CXCL7/PD-L1 axis were identified in TNBC cells, which boost metastatic niches and immunosuppressive microenvironments. MCT-1high/PD-L1high/CXCL7high and CXCL7high/IL-6high/IL-6Rhigh expression patterns predict worse prognosis and poorer survival in breast cancer patients. IL-6R-based immunotherapy more effectively prevented postsurgical TNBC metastasis, recurrence and mortality than anti-PD-L1 immunotherapy. Anti-IL-6R improved helper T, cytotoxic T and natural killer (NK) cells in lymphatic system and decreased Tregs in the recurrent and metastatic tumors, but anti-PD-L1 incapably elevated NK cells. Combined IL-6R and PD-L1 immunotherapies abridged TNBC cell stemness and M2 macrophage activity better than monotherapy. Sequential immunotherapy of PD-L1 and IL-6R demonstrated the best survival outcome, lowest postoperative recurrence and metastasis than synchronized therapy, particularly in shMCT-1 context. Conclusion: Systemic targeting of the MCT-1/IL-6/IL-6R/CXCL7/PD-L1 interconnection enhances the immune surveillance that inhibits aggressiveness of TNBC. Citation Format: Aushia Tanzih Al Haq, Pao-Pao Yang, Christopher Jin, Jou-Ho Shih, Li-Mei Chen, Lu-Hai Wang, Michael P. Snyder, Hsin-Ling Hsu. Immunotherapy of IL-6R Prevents Relapse and Metastasis of Triple-Negative Breast Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A022.