Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor-resistant HER2-positive breast cancer

• Published in: Nature communications Vol. 10; no. 1; pp. 3817 - 12
• Main Authors: Wang, Qingfei, Guldner, Ian H., Golomb, Samantha M., Sun, Longhua, Harris, Jack A., Lu, Xin, Zhang, Siyuan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-08-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 45/91; 631/1647/514/1949; 631/67/327; 64/60; Animals; Antibodies; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Breast cancer; Cell Line, Tumor; Clinical trials; Combinatorial analysis; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Drug resistance; Drug Resistance, Neoplasm - drug effects; Enzyme inhibitors; ErbB-2 protein; Evolution; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - immunology; Humanities and Social Sciences; Immune checkpoint; Immunity; Immunotherapy; Inhibitors; Kinases; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - pathology; Mice; Mice, Transgenic; Models, Biological; multidisciplinary; Myeloid Progenitor Cells - drug effects; Myeloid Progenitor Cells - immunology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Science; Science (multidisciplinary); Single-Cell Analysis; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Target acquisition; Treatment Outcome; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumors; Tyrosine; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11729-1

Acquired resistance to targeted cancer therapy is a significant clinical challenge. In parallel with clinical trials combining CDK4/6 inhibitors to treat HER2+ breast cancer, we sought to prospectively model tumor evolution in response to this regimen in vivo and identify a clinically actionable strategy to combat drug resistance. Despite a promising initial response, acquired resistance emerges rapidly to the combination of anti-HER2/neu antibody and CDK4/6 inhibitor Palbociclib. Using high-throughput single-cell profiling over the course of treatments, we reveal a distinct immunosuppressive immature myeloid cell (IMC) population to infiltrate the resistant tumors. Guided by single-cell transcriptome analysis, we demonstrate that combination of IMC-targeting tyrosine kinase inhibitor cabozantinib and immune checkpoint blockade enhances anti-tumor immunity, and overcomes the resistance. Furthermore, sequential combinatorial immunotherapy enables a sustained control of the fast-evolving CDK4/6 inhibitor-resistant tumors. Our study demonstrates a translational framework for treating rapidly evolving tumors through preclinical modeling and single-cell analyses.
The benefit of combined CDK4/6 and anti-HER2 therapy in breast cancer is limited due to acquired resistance. Here, the authors perform single-cell analysis and show an immature myeloid cell population to infiltrate resistant tumors, and that combined cabozantinib and checkpoint therapy overcome this resistance with a sustained efficacy.