Local, multimodal intralesional therapy renders distant brain metastases susceptible to PD-L1 blockade in a preclinical model of triple-negative breast cancer

Abstract Despite recent progress in therapeutic strategies, prognosis of metastatic triple-negative breast cancer (TNBC) remains dismal. Evidence suggests that the induction and activation of tumor-residing conventional type-1 dendritic cells (cDC1s) is critical for the generation of CD8+ T cells th...

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Autores principales:	Toshihiro Yokoi, Takaaki Oba, Ryutaro Kajihara, Scott I. Abrams, Fumito Ito
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a47ce881037545fd9257a49e41ccbe12
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spelling	oai:doaj.org-article:a47ce881037545fd9257a49e41ccbe122021-11-14T12:20:28ZLocal, multimodal intralesional therapy renders distant brain metastases susceptible to PD-L1 blockade in a preclinical model of triple-negative breast cancer10.1038/s41598-021-01455-42045-2322https://doaj.org/article/a47ce881037545fd9257a49e41ccbe122021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01455-4https://doaj.org/toc/2045-2322Abstract Despite recent progress in therapeutic strategies, prognosis of metastatic triple-negative breast cancer (TNBC) remains dismal. Evidence suggests that the induction and activation of tumor-residing conventional type-1 dendritic cells (cDC1s) is critical for the generation of CD8+ T cells that mediate the regression of mammary tumors and potentiate anti-PD-1/PD-L1 therapeutic efficacy. However, it remains unknown whether this strategy is effective against metastatic TNBC, which is poorly responsive to immunotherapy. Here, using a mouse model of TNBC, we established orthotopic mammary tumors and brain metastases, and treated mammary tumors with in situ immunomodulation (ISIM) consisting of intratumoral injections of Flt3L to mobilize cDC1s, local irradiation to induce immunogenic tumor cell death, and TLR3/CD40 stimulation to activate cDC1s. ISIM treatment of the mammary tumor increased circulating T cells with effector phenotypes, and infiltration of CD8+ T cells into the metastatic brain lesions, resulting in delayed progression of brain metastases and improved survival. Furthermore, although anti-PD-L1 therapy alone was ineffective against brain metastases, ISIM overcame resistance to anti-PD-L1 therapy, which rendered these tumor-bearing mice responsive to anti-PD-L1 therapy and further improved survival. Collectively, these results illustrate the therapeutic potential of multimodal intralesional therapy for patients with unresectable and metastatic TNBC.Toshihiro YokoiTakaaki ObaRyutaro KajiharaScott I. AbramsFumito ItoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Toshihiro Yokoi Takaaki Oba Ryutaro Kajihara Scott I. Abrams Fumito Ito Local, multimodal intralesional therapy renders distant brain metastases susceptible to PD-L1 blockade in a preclinical model of triple-negative breast cancer
description	Abstract Despite recent progress in therapeutic strategies, prognosis of metastatic triple-negative breast cancer (TNBC) remains dismal. Evidence suggests that the induction and activation of tumor-residing conventional type-1 dendritic cells (cDC1s) is critical for the generation of CD8+ T cells that mediate the regression of mammary tumors and potentiate anti-PD-1/PD-L1 therapeutic efficacy. However, it remains unknown whether this strategy is effective against metastatic TNBC, which is poorly responsive to immunotherapy. Here, using a mouse model of TNBC, we established orthotopic mammary tumors and brain metastases, and treated mammary tumors with in situ immunomodulation (ISIM) consisting of intratumoral injections of Flt3L to mobilize cDC1s, local irradiation to induce immunogenic tumor cell death, and TLR3/CD40 stimulation to activate cDC1s. ISIM treatment of the mammary tumor increased circulating T cells with effector phenotypes, and infiltration of CD8+ T cells into the metastatic brain lesions, resulting in delayed progression of brain metastases and improved survival. Furthermore, although anti-PD-L1 therapy alone was ineffective against brain metastases, ISIM overcame resistance to anti-PD-L1 therapy, which rendered these tumor-bearing mice responsive to anti-PD-L1 therapy and further improved survival. Collectively, these results illustrate the therapeutic potential of multimodal intralesional therapy for patients with unresectable and metastatic TNBC.
format	article
author	Toshihiro Yokoi Takaaki Oba Ryutaro Kajihara Scott I. Abrams Fumito Ito
author_facet	Toshihiro Yokoi Takaaki Oba Ryutaro Kajihara Scott I. Abrams Fumito Ito
author_sort	Toshihiro Yokoi
title	Local, multimodal intralesional therapy renders distant brain metastases susceptible to PD-L1 blockade in a preclinical model of triple-negative breast cancer
title_short	Local, multimodal intralesional therapy renders distant brain metastases susceptible to PD-L1 blockade in a preclinical model of triple-negative breast cancer
title_full	Local, multimodal intralesional therapy renders distant brain metastases susceptible to PD-L1 blockade in a preclinical model of triple-negative breast cancer
title_fullStr	Local, multimodal intralesional therapy renders distant brain metastases susceptible to PD-L1 blockade in a preclinical model of triple-negative breast cancer
title_full_unstemmed	Local, multimodal intralesional therapy renders distant brain metastases susceptible to PD-L1 blockade in a preclinical model of triple-negative breast cancer
title_sort	local, multimodal intralesional therapy renders distant brain metastases susceptible to pd-l1 blockade in a preclinical model of triple-negative breast cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a47ce881037545fd9257a49e41ccbe12
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Local, multimodal intralesional therapy renders distant brain metastases susceptible to PD-L1 blockade in a preclinical model of triple-negative breast cancer

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