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Sequence of androgen receptor-targeted vaccination with androgen deprivation therapy affects anti-prostate tumor efficacy.
- Source :
-
Journal for immunotherapy of cancer [J Immunother Cancer] 2024 May 20; Vol. 12 (5). Date of Electronic Publication: 2024 May 20. - Publication Year :
- 2024
-
Abstract
- Rationale: Androgen deprivation therapy (ADT) is the primary treatment for recurrent and metastatic prostate cancer. In addition to direct antitumor effects, ADT has immunomodulatory effects such as promoting T-cell infiltration and enhancing antigen processing/presentation. Previous studies in our laboratory have demonstrated that ADT also leads to increased expression of the androgen receptor (AR) and increased recognition of prostate tumor cells by AR-specific CD8+T cells. We have also demonstrated that ADT combined with a DNA vaccine encoding the AR significantly slowed tumor growth and improved the survival of prostate tumor-bearing mice. The current study aimed to investigate the impact of the timing and sequencing of ADT with vaccination on the tumor immune microenvironment in murine prostate cancer models to further increase the antitumor efficacy of vaccines.<br />Methods: Male FVB mice implanted with Myc-CaP tumor cells, or male C57BL/6 mice implanted with TRAMP-C1 prostate tumor cells, were treated with a DNA vaccine encoding AR (pTVG-AR) and ADT. The sequence of administration was evaluated for its effect on tumor growth, and tumor-infiltrating immune populations were characterized.<br />Results: Vaccination prior to ADT (pTVG-AR → ADT) significantly enhanced antitumor responses and survival. This was associated with increased tumor infiltration by CD4+ and CD8+ T cells, including AR-specific CD8+T cells. Depletion of CD8+T cells prior to ADT significantly worsened overall survival. Following ADT treatment, however, Gr1+ myeloid-derived suppressor cells (MDSCs) increased, and this was associated with fewer infiltrating T cells and reduced tumor growth. Inhibiting Gr1+MDSCs recruitment, either by using a CXCR2 antagonist or by cycling androgen deprivation with testosterone replacement, improved antitumor responses and overall survival.<br />Conclusion: Vaccination prior to ADT significantly improved antitumor responses, mediated in part by increased infiltration of CD8+T cells following ADT. Targeting MDSC recruitment following ADT further enhanced antitumor responses. These findings suggest logical directions for future clinical trials to improve the efficacy of prostate cancer vaccines.<br />Competing Interests: Competing interests: DGM has an ownership interest, has received research support and serves as a consultant to Madison Vaccines, which has licensed material described in this manuscript. None of the other authors have relevant potential conflicts of interest.<br /> (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Subjects :
- Male
Animals
Mice
Vaccines, DNA therapeutic use
Vaccines, DNA pharmacology
Androgen Antagonists therapeutic use
Androgen Antagonists pharmacology
Cell Line, Tumor
Mice, Inbred C57BL
Vaccination
Humans
Tumor Microenvironment
Disease Models, Animal
CD8-Positive T-Lymphocytes immunology
Prostatic Neoplasms drug therapy
Prostatic Neoplasms immunology
Prostatic Neoplasms pathology
Receptors, Androgen metabolism
Cancer Vaccines therapeutic use
Cancer Vaccines pharmacology
Cancer Vaccines immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2051-1426
- Volume :
- 12
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal for immunotherapy of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 38772685
- Full Text :
- https://doi.org/10.1136/jitc-2024-008848