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

Obradovic, Aleksandar Zoran; Dallos, Matthew C.; Zahurak, Marianna L.; Partin, Alan W.; Schaeffer, Edward M.; Ross, Ashley E.; Allaf, Mohamad E.; Nirschl, Thomas R.; 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.

Purpose: 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.

Experimental Design: Therefore, we conducted a neoadjuvant, randomized study to quantify the immunologic effects of a granulocyte-macrophage colony-stimulating factor (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.

Results: Both Cy/GVAX plus degarelix and degarelix alone led to significant increases in intratumoral CD8+ T cell infiltration and PD-L1 expression as compared to 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 to degarelix alone. Gene expression profiling demonstrated that CHIT1, a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared to degarelix alone.

Conclusions: 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.

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Also Published In

Title
Clinical Cancer Research
DOI
https://doi.org/10.1158/1078-0432.CCR-19-3372

More About This Work

Academic Units
Medicine
Cellular, Molecular and Biophysical Studies
Published Here
April 3, 2020