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

Mariya Rozenblit, Wouter R. Hendrickx, Adriana Heguy, Luis Chiriboga, Cynthia Loomis, Karina Ray, Farbod Darvishian, Mikala Egeblad, Sandra Demaria, Francesco M. Marincola, Davide Bedognetti, Sylvia Adams

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number8572
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

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imiquimod
Skin Neoplasms
Breast Neoplasms
Neoplasm Metastasis
Neoplasms
Up-Regulation
Toll-Like Receptor 7
Th1 Cells
Basal Cell Carcinoma
Antigen Presentation
Chemokines
Immunotherapy
Melanoma
Leukocytes

ASJC Scopus subject areas

  • General

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Transcriptomic profiles conducive to immune-mediated tumor rejection in human breast cancer skin metastases treated with Imiquimod. / Rozenblit, Mariya; Hendrickx, Wouter R.; Heguy, Adriana; Chiriboga, Luis; Loomis, Cynthia; Ray, Karina; Darvishian, Farbod; Egeblad, Mikala; Demaria, Sandra; Marincola, Francesco M.; Bedognetti, Davide; Adams, Sylvia.

In: Scientific reports, Vol. 9, No. 1, 8572, 01.12.2019.

Research output: Contribution to journalArticle

Rozenblit, M, Hendrickx, WR, Heguy, A, Chiriboga, L, Loomis, C, Ray, K, Darvishian, F, Egeblad, M, Demaria, S, Marincola, FM, Bedognetti, D & Adams, S 2019, 'Transcriptomic profiles conducive to immune-mediated tumor rejection in human breast cancer skin metastases treated with Imiquimod', Scientific reports, vol. 9, no. 1, 8572. https://doi.org/10.1038/s41598-019-42784-9
Rozenblit, Mariya ; Hendrickx, Wouter R. ; Heguy, Adriana ; Chiriboga, Luis ; Loomis, Cynthia ; Ray, Karina ; Darvishian, Farbod ; Egeblad, Mikala ; Demaria, Sandra ; Marincola, Francesco M. ; Bedognetti, Davide ; Adams, Sylvia. / Transcriptomic profiles conducive to immune-mediated tumor rejection in human breast cancer skin metastases treated with Imiquimod. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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