Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer

Abstract We show that treatment with the FDA-approved anti-parasitic drug ivermectin induces immunogenic cancer cell death (ICD) and robust T cell infiltration into breast tumors. As an allosteric modulator of the ATP/P2X4/P2X7 axis which operates in both cancer and immune cells, ivermectin also sel...

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Autores principales:	Dobrin Draganov, Zhen Han, Aamir Rana, Nitasha Bennett, Darrell J. Irvine, Peter P. Lee
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/579a462d3ea242dea38063229ef786e8
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spelling	oai:doaj.org-article:579a462d3ea242dea38063229ef786e82021-12-02T15:52:55ZIvermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer10.1038/s41523-021-00229-52374-4677https://doaj.org/article/579a462d3ea242dea38063229ef786e82021-03-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00229-5https://doaj.org/toc/2374-4677Abstract We show that treatment with the FDA-approved anti-parasitic drug ivermectin induces immunogenic cancer cell death (ICD) and robust T cell infiltration into breast tumors. As an allosteric modulator of the ATP/P2X4/P2X7 axis which operates in both cancer and immune cells, ivermectin also selectively targets immunosuppressive populations including myeloid cells and Tregs, resulting in enhanced Teff/Tregs ratio. While neither agent alone showed efficacy in vivo, combination therapy with ivermectin and checkpoint inhibitor anti-PD1 antibody achieved synergy in limiting tumor growth (p = 0.03) and promoted complete responses (p < 0.01), also leading to immunity against contralateral re-challenge with demonstrated anti-tumor immune responses. Going beyond primary tumors, this combination achieved significant reduction in relapse after neoadjuvant (p = 0.03) and adjuvant treatment (p < 0.001), and potential cures in metastatic disease (p < 0.001). Statistical modeling confirmed bona fide synergistic activity in both the adjuvant (p = 0.007) and metastatic settings (p < 0.001). Ivermectin has dual immunomodulatory and ICD-inducing effects in breast cancer, converting cold tumors hot, thus represents a rational mechanistic partner with checkpoint blockade.Dobrin DraganovZhen HanAamir RanaNitasha BennettDarrell J. IrvinePeter P. LeeNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Dobrin Draganov Zhen Han Aamir Rana Nitasha Bennett Darrell J. Irvine Peter P. Lee Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer
description	Abstract We show that treatment with the FDA-approved anti-parasitic drug ivermectin induces immunogenic cancer cell death (ICD) and robust T cell infiltration into breast tumors. As an allosteric modulator of the ATP/P2X4/P2X7 axis which operates in both cancer and immune cells, ivermectin also selectively targets immunosuppressive populations including myeloid cells and Tregs, resulting in enhanced Teff/Tregs ratio. While neither agent alone showed efficacy in vivo, combination therapy with ivermectin and checkpoint inhibitor anti-PD1 antibody achieved synergy in limiting tumor growth (p = 0.03) and promoted complete responses (p < 0.01), also leading to immunity against contralateral re-challenge with demonstrated anti-tumor immune responses. Going beyond primary tumors, this combination achieved significant reduction in relapse after neoadjuvant (p = 0.03) and adjuvant treatment (p < 0.001), and potential cures in metastatic disease (p < 0.001). Statistical modeling confirmed bona fide synergistic activity in both the adjuvant (p = 0.007) and metastatic settings (p < 0.001). Ivermectin has dual immunomodulatory and ICD-inducing effects in breast cancer, converting cold tumors hot, thus represents a rational mechanistic partner with checkpoint blockade.
format	article
author	Dobrin Draganov Zhen Han Aamir Rana Nitasha Bennett Darrell J. Irvine Peter P. Lee
author_facet	Dobrin Draganov Zhen Han Aamir Rana Nitasha Bennett Darrell J. Irvine Peter P. Lee
author_sort	Dobrin Draganov
title	Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer
title_short	Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer
title_full	Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer
title_fullStr	Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer
title_full_unstemmed	Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer
title_sort	ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/579a462d3ea242dea38063229ef786e8
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Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer

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