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.
Highlights
Breast cancer is the second cause of death in women and the second most common cancer to metastasize to the skin after melanoma[1]
Several case reports have shown regression of cutaneous metastases with imiquimod either alone[18,19] or in combination with other therapies[20,21,22]. This tumor regression was associated with an increase in T cell infiltrate and upregulation of Immunologic Constant of Rejection (ICR) genes such as CCL5, CXCL9, CXCL10 important for homing of cytotoxic T cells as well as markers of dendritic cell (CD80, CD86) and T cell activation (CD69)[23]
We have previously shown that topical imiquimod, as a single agent, can induce an antitumor response in 20% of skin metastases of mainly hormone receptor positive breast cancers and can promote an immunogenic tumor microenvironment[35]
Summary
Breast cancer is the second cause of death in women and the second most common cancer to metastasize to the skin after melanoma[1]. Genome-wide transcriptomic analysis of basal cell carcinoma before and after treatment has defined key molecular events induced by imiquimod[7] Such transcripts are involved in the activation of specific chemokine-chemokine receptor ligand pathways conducive to a T-helper 1 (Th-1) immune response and the induction of immune-effector genes. Several case reports have shown regression of cutaneous metastases with imiquimod either alone[18,19] or in combination with other therapies[20,21,22] This tumor regression was associated with an increase in T cell infiltrate and upregulation of ICR genes such as CCL5, CXCL9, CXCL10 important for homing of cytotoxic T cells as well as markers of dendritic cell (CD80, CD86) and T cell activation (CD69)[23]. Imiquimod may play an even more important role in hormone receptor positive breast cancer, since it is the subtype with the least amount of CD8+ infiltrating T cells[34]
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