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Sci Rep. 2019 Jun 12;9(1):8572. doi: 10.1038/s41598-019-42784-9.

Transcriptomic profiles conducive to immune-mediated tumor rejection in human breast cancer skin metastases treated with Imiquimod.

Author information

1
Department of Hematology Oncology, Yale University School of Medicine, New Haven, Connecticut, USA.
2
Tumor Biology, Immunology, and Therapy Section, Immunology, Inflammation, and Metabolism Department, Division of Translational Medicine, Sidra Medicine, Doha, Qatar.
3
Department of Pathology, New York University School of Medicine, New York, New York, USA.
4
Genome Technology Center, Division of Advanced Research Technologies, University of New York School of Medicine, New York, New York, USA.
5
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, New York, USA.
6
Department of Radiation Oncology Weill Cornell Medical College, New York, New York, USA.
7
Refuge Biotechnologies Inc, Menlo Park, CA, USA.
8
Tumor Biology, Immunology, and Therapy Section, Immunology, Inflammation, and Metabolism Department, Division of Translational Medicine, Sidra Medicine, Doha, Qatar. dbedognetti@sidra.org.
9
Laura & Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, New York, USA. Sylvia.Adams@nyumc.org.

Abstract

Imiquimod is a topical toll-like-receptor-7 agonist currently used for treating basal cell carcinoma. Recently, imiquimod has demonstrated tumor regression in melanoma and breast cancer skin metastases. However, the molecular perturbations induced by imiquimod in breast cancer metastases have not been previously characterized. Here, we describe transcriptomic profiles associated with responsiveness to imiquimod in breast cancer skin metastases. Baseline and post-treatment tumor samples from patients treated with imiquimod in a clinical trial were profiled using Nanostring technology. Through an integrative analytic pipeline, we showed that tumors from patients who achieved a durable clinical response displayed a permissive microenvironment, substantiated by the upregulation of transcripts encoding for molecules involved in leukocyte adhesion and migration, cytotoxic functions, and antigen presentation. In responding patients, Imiquimod triggered a strong T-helper-1 (Th-1)/cytotoxic immune response, characterized by the coordinated upregulation of Th-1 chemokines, migration of Th-1 and cytotoxic T cells into the tumor, and activation of immune-effector functions, ultimately mediating tumor destruction. In conclusion, we have shown that topical imiquimod can induce a robust immune response in breast cancer metastases, and this response is more likely to occur in tumors with a pre-activated microenvironment. In this setting, imiquimod could be utilized in combination with other targeted immunotherapies to increase therapeutic efficacy.

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