CHA1: A New Combinatorial Therapy That Reciprocally Regulates Wnt and JAK/STAT/Interferon Signaling to Re-program Breast Tumors and the Tumor-Resident Landscape
CHA1: A New Combinatorial Therapy That Reciprocally Regulates Wnt and JAK/STAT/Interferon Signaling to Re-program Breast Tumors and the Tumor-Resident Landscape
ABSTRACT Triple negative breast cancers (TNBC) pose exceptional challenges with fatal brain metastases as a clear and unmet need. Immune checkpoint inhibitors (ICIs) are promising therapeutic strategies, but most TNBC are resistant, or “cold” tumors, due to lack of tumor-resident immune engagement. No FDA-approved therapies exist which promote a “cold-to-hot” transition or induce the important biomarker PD-L1, often used for ICI clinical decision-making. Maximal ICI susceptibility, or a full “cold-to-hot” transition, requires reciprocal Wnt signaling inhibition and Jak/STAT/interferon signaling activation. We report a new compound combination (CHA1) that fits the above criteria. CHA1 is comprised of EGCG (epigallocatechin-3-gallate; green-tea compound) and decitabine (DNA-methyltransferase (DNMT1) inhibitor; 5’deaza-cytidine; FDA-approved for hematologic malignancies). We used immune-compromised and syngeneic TNBC pre-clinical models to investigate tumor-intrinsic and tumor-resident T-cell effects, respectively. All results required CHA1 (but not EGCG or decitabine alone) and utilized attainable human dose equivalences with manageable safety profiles. CHA1 triggered efficient Wnt signaling inhibition by elevating Wnt pathway inhibitors (HBP1 and SFRP1) and traversed the blood-brain barrier to reduce both tumor and brain metastatic growth. Transcriptomic and expression analyses revealed that CHA1 treatment effectuated a robust tumor-intrinsic JAK/STAT/IFN response 1) to induce PDL1 and 2) to induce antigen presentation and processing genes, including MHC-1, MHC-2 and numerous genes attributed to professional antigen-presenting cells; 3) to induce CD8+-T-cell infiltration and activation. Additionally, CHA1 pre-treatment improved anti-PDL1 efficacy in a syngeneic setting. Lastly, we derived a composite gene signature emblematic of CHA1 treatment and of a favorable clinical prognosis in-silico. Together, our work supports a model in which CHA1 influences epigenetics, Wnt and Jak/STAT/IFN signaling mechanisms—all to reprogram an epithelial-mesenchymal TNBC tumor to express antigen-presenting properties and to recruit and activate tumor-resident CD8+-T-cells. We discuss our findings in the context of cancer biology and immunity with implications for improving ICI susceptibility for TNBC.
Chipman Mollie、Bogis Ahlam Mukhtar、Zhang Rui、Casta?er Maricel、Triafallou George、Yee Amy S.、Carland Corinne、Lee AJ. Jaehoon、Li Kaiqi、Alqurashi Roaya S.、Deieso-Frechette Francesca、Paulson K. Eric、Alamoudi Mariam K.、Gillani Kyle、Herbosa Christopher G.
Department of Developmental, Molecular and Chemical Biology, Tufts University School of MedicineProgram in Pharmacology and Experimental Therapeutics, Graduate School of Biomedical Sciences, Boston||Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine||Pharmacology and Toxicology Department, College of Pharmacy, Umm Al-Qura UniversityDepartment of Developmental, Molecular and Chemical Biology, Tufts University School of MedicineDepartment of Developmental, Molecular and Chemical Biology, Tufts University School of MedicineDepartment of Developmental, Molecular and Chemical Biology, Tufts University School of MedicineProgram in Pharmacology and Experimental Therapeutics, Graduate School of Biomedical Sciences, Boston||Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine||Program in Biomedical Sciences, Tufts University School of Medicine BostonDepartment of Developmental, Molecular and Chemical Biology, Tufts University School of MedicineDepartment of Developmental, Molecular and Chemical Biology, Tufts University School of MedicineDepartment of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine||Program in Biomedical Sciences, Tufts University School of Medicine BostonProgram in Pharmacology and Experimental Therapeutics, Graduate School of Biomedical Sciences, Boston||Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine||Pharmacology and Toxicology Department, College of Pharmacy, Umm Al-Qura UniversityDepartment of Developmental, Molecular and Chemical Biology, Tufts University School of MedicineProgram in Pharmacology and Experimental Therapeutics, Graduate School of Biomedical Sciences, Boston||Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine||Program in Biomedical Sciences, Tufts University School of Medicine BostonProgram in Pharmacology and Experimental Therapeutics, Graduate School of Biomedical Sciences, Boston||Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine||Pharmacology and Toxicology Department, College of Pharmacy, Prince Sattam bin Abdulaziz UniversityDepartment of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine||Program in Biomedical Sciences, Tufts University School of Medicine BostonDepartment of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine
肿瘤学药学分子生物学
Chipman Mollie,Bogis Ahlam Mukhtar,Zhang Rui,Casta?er Maricel,Triafallou George,Yee Amy S.,Carland Corinne,Lee AJ. Jaehoon,Li Kaiqi,Alqurashi Roaya S.,Deieso-Frechette Francesca,Paulson K. Eric,Alamoudi Mariam K.,Gillani Kyle,Herbosa Christopher G..CHA1: A New Combinatorial Therapy That Reciprocally Regulates Wnt and JAK/STAT/Interferon Signaling to Re-program Breast Tumors and the Tumor-Resident Landscape[EB/OL].(2025-03-28)[2025-04-28].https://www.biorxiv.org/content/10.1101/2022.03.25.485706.点此复制
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