T-Cell Infiltration and Adaptive Treg Resistance in Response to Androgen Deprivation With or Without Vaccination in Localized Prostate Cancer

Previous studies suggest that androgen deprivation therapy (ADT) promotes antitumor immunity in prostate cancer. Whether a vaccine-based approach can augment this effect remains unknown. We conducted a neoadjuvant, randomized study to quantify the immunologic effects of a GM-CSF-secreting allogeneic...

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Bibliographic Details
Published in:Clinical cancer research 2020-07, Vol.26 (13), p.3182-3192
Main Authors: Obradovic, Aleksandar Z, Dallos, Matthew C, Zahurak, Marianna L, Partin, Alan W, Schaeffer, Edward M, Ross, Ashley E, Allaf, Mohamad E, Nirschl, Thomas R, Liu, David, Chapman, Carolyn G, O'Neal, Tanya, Cao, Haiyi, Durham, Jennifer N, Guner, Gunes, Baena-Del Valle, Javier A, Ertunc, Onur, De Marzo, Angelo M, Antonarakis, Emmanuel S, Drake, Charles G
Format: Article
Language:English
Subjects:
Aged
Androgen Antagonists - pharmacology
Androgen Antagonists - therapeutic use
Biomarkers, Tumor
Cancer Vaccines - administration & dosage
Cancer Vaccines - adverse effects
Cancer Vaccines - therapeutic use
Combined Modality Therapy
Humans
Lymphocytes, Tumor-Infiltrating - immunology
Lymphocytes, Tumor-Infiltrating - metabolism
Lymphocytes, Tumor-Infiltrating - pathology
Male
Middle Aged
Neoplasm Grading
Neoplasm Staging
Prostatic Neoplasms - diagnosis
Prostatic Neoplasms - immunology
Prostatic Neoplasms - mortality
Prostatic Neoplasms - therapy
Recurrence
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - metabolism
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
T-Lymphocytes, Regulatory - pathology
Treatment Outcome
Tumor Microenvironment - immunology
Vaccination
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Summary:Previous studies suggest that androgen deprivation therapy (ADT) promotes antitumor immunity in prostate cancer. Whether a vaccine-based approach can augment this effect remains unknown. We conducted a neoadjuvant, randomized study to quantify the immunologic effects of a GM-CSF-secreting allogeneic cellular vaccine in combination with low-dose cyclophosphamide (Cy/GVAX) followed by degarelix versus degarelix alone in patients with high-risk localized prostate adenocarcinoma who were planned for radical prostatectomy. Both Cy/GVAX plus degarelix and degarelix alone led to significant increases in intratumoral CD8 T-cell infiltration and PD-L1 expression as compared with a cohort of untreated, matched controls. However, the CD8 T-cell infiltrate was accompanied by a proportional increase in regulatory T cells (Treg), suggesting that adaptive Treg resistance may dampen the immunogenicity of ADT. Although Cy/GVAX followed by degarelix was associated with a modest improvement in time-to-PSA progression and time-to-next treatment, as well as an increase in PD-L1, there was no difference in the CD8 T-cell infiltrate as compared with degarelix alone. Gene expression profiling demonstrated that , a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared with degarelix alone. Our results highlight that ADT with or without Cy/GVAX induces a complex immune response within the prostate tumor microenvironment. These data have important implications for combining ADT with immunotherapy. In particular, our finding that ADT increases both CD8 T cells and Tregs supports the development of regimens combining ADT with Treg-depleting agents in the treatment of prostate cancer.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-19-3372