https://scholars.lib.ntu.edu.tw/handle/123456789/551188
標題: | Combining intratumoral Treg depletion with androgen deprivation therapy (ADT): Preclinical activity in the Myc-CaP model | 作者: | Ying-Chun Shen Ghasemzadeh A. Kochel C.M. Nirschl T.R. Francica B.J. Lopez-Bujanda Z.A. Carrera Haro M.A. Tam A. Anders R.A. Selby M.J. Korman A.J. Drake C.G. |
公開日期: | 2018 | 出版社: | Nature Publishing Group | 卷: | 21 | 期: | 1 | 起(迄)頁: | 113-125 | 來源出版物: | Prostate Cancer and Prostatic Diseases | 摘要: | Background: Immune checkpoint blockade has shown promising antitumor activity against a variety of tumor types. However, responses in castration-resistant prostate cancer remain relatively rare - potentially due to low baseline levels of infiltration. Using an immunocompetent cMyc-driven model (Myc-CaP), we sought to understand the immune infiltrate induced by androgen deprivation therapy (ADT) and to leverage that infiltration toward therapeutic benefit. Methods: Using flow cytometry, qPCR and IHC, we quantified ADT-induced immune infiltration in terms of cell type and function. Preclinical treatment studies tested the combinatorial effects of ADT and immune checkpoint blockade using tumor outgrowth and overall survival as end points. Results: ADT induces a complex pro-inflammatory infiltrate. This pro-inflammatory infiltrate was apparent in the early postcastration period but diminished as castration resistance emerged. Combining ADT with tumor-infiltrating regulatory T cell (Treg) depletion using a depleting anti-CTLA-4 antibody significantly delayed the development of castration resistance and prolonged survival of a fraction of tumor-bearing mice. Immunotherapy as a monotherapy failed to provide a survival benefit and was ineffective if not administered in the peri-castration period. Conclusions: The immune infiltrate induced by ADT is diverse and varies over time. Therapeutic strategies focusing on depleting Tregs in the peri-castration period are of particular interest. ? 2018 The Author(s), under exclusive licence to Macmillan Publishers Limited, part of Springer Nature. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85036573824&doi=10.1038%2fs41391-017-0013-x&partnerID=40&md5=d3a62b8ccb40b51cca81a1b2a6179280 https://scholars.lib.ntu.edu.tw/handle/123456789/551188 |
ISSN: | 1365-7852 | DOI: | 10.1038/s41391-017-0013-x | SDG/關鍵字: | cytotoxic T lymphocyte antigen 4; cytotoxic T lymphocyte antigen 4 antibody; degarelix; gamma interferon; granzyme B; immunological antineoplastic agent; interleukin 2; messenger RNA; programmed death 1 receptor; testosterone; tumor necrosis factor; androgen; cytotoxic T lymphocyte antigen 4; androgen deprivation therapy; animal cell; animal experiment; animal model; animal tissue; Article; cancer growth; cancer inhibition; cancer resistance; castration; CD4+ T lymphocyte; CD8+ T lymphocyte; controlled study; cytokine production; flow cytometry; immunocompetence; immunohistochemistry; inflammatory infiltrate; long term survival; lymphocytic infiltration; male; mouse; nonhuman; orchiectomy; overall survival; polymerase chain reaction; preclinical study; priority journal; prostate cancer; regulatory T lymphocyte; survival time; T cell depletion; testosterone blood level; tumor microenvironment; animal; castration resistant prostate cancer; drug screening; human; immunology; immunotherapy; metabolism; pathology; regulatory T lymphocyte; tumor cell line; Androgens; Animals; Cell Line, Tumor; CTLA-4 Antigen; Flow Cytometry; Humans; Immunotherapy; Male; Mice; Orchiectomy; Prostatic Neoplasms, Castration-Resistant; T-Lymphocytes, Regulatory; Xenograft Model Antitumor Assays |
顯示於: | 醫學院附設醫院 (臺大醫院) |
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