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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.

YOKOI Toshihiro OBA Takaaki KAJIHARA Ryutaro ABRAMS Scott I. ITO Fumito 滋賀医科大学

2021.11.09

概要

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.

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Acknowledgements

We acknowledge Drs. Tibor Keler and Henry Marsh in Celldex Therapeutics, Inc. for providing hFlt3L for this

study, BioRender.com for illustrations, and the Division of Laboratory Animal Resources, and Pathology Network

(Roswell Park) for technical assistance. This work was supported by Roswell Park Comprehensive Cancer Center

and National Cancer Institute Grant P30CA016056 involving the use of Roswell Park’s Flow and Image Cytometry

Shared Resource, Pathology Network, and the Onsite Supply Center, METAvivor and National Cancer Institute

Grant K08CA197966 and R01CA255240-01A1 [to F.I.] and R01CA172105 [to S.I.A.]. T.O. was supported by

Uehara Memorial Foundation.

Author contributions

T.Y. contributed development of methodology, acquisition of data, analysis and interpretation of data, writing,

and review of the manuscript. T.O. contributed development of methodology, acquisition of data, analysis and

interpretation of data, review, and revision of the manuscript. R.K. contributed acquisition of data, analysis and

interpretation of data, review, and revision of the manuscript. S.A. provided reagents (AT-3 tumors), and revised

the article. F.I. developed the concept and methodology, analyzed data, coordinated author activities, revised the

manuscript, and provided final approval of the version to be submitted.

Competing interests The authors declare no competing interests.

Additional information

Supplementary Information The online version contains supplementary material available at https://​doi.​org/​

10.​1038/​s41598-​021-​01455-4.

Correspondence and requests for materials should be addressed to F.I.

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