Combining intratumoral Treg depletion with androgen deprivation therapy (ADT): Preclinical activity in the Myc-CaP model
Journal
Prostate Cancer and Prostatic Diseases
Journal Volume
21
Journal Issue
1
Pages
113-125
Date Issued
2018
Author(s)
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.
Abstract
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.
SDGs
Other Subjects
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
Publisher
Nature Publishing Group
Type
journal article