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

被引:79
作者
Obradovic, Aleksandar Z. [1 ]
Dallos, Matthew C. [2 ]
Zahurak, Marianna L. [3 ]
Partin, Alan W. [4 ]
Schaeffer, Edward M. [5 ]
Ross, Ashley E. [6 ]
Allaf, Mohamad E. [4 ]
Nirschl, Thomas R. [7 ]
Liu, David [8 ,9 ]
Chapman, Carolyn G. [7 ]
O'Neal, Tanya [7 ]
Cao, Haiyi [7 ]
Durham, Jennifer N. [7 ]
Guner, Gunes [10 ]
Baena-Del Valle, Javier A. [10 ]
Ertunc, Onur [10 ]
De Marzo, Angelo M. [10 ]
Antonarakis, Emmanuel S. [7 ]
Drake, Charles G. [1 ,2 ,4 ]
机构
[1] Columbia Univ, Columbia Ctr Translat Immunol, Irving Med Ctr, New York, NY USA
[2] Columbia Univ, Med Ctr, Herbert Irving Comprehens Canc, Div Hematol & Oncol, New York, NY USA
[3] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol & Biostat, Baltimore, MD USA
[4] Johns Hopkins Univ, Brady Urol Inst, Dept Urol, Baltimore, MD USA
[5] Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA
[6] Texas Urol Specialists, Dallas, TX USA
[7] Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD USA
[8] Dana Farber Canc Inst, Boston, MA 02115 USA
[9] Broad Inst Harvard & MIT, Cambridge, MA USA
[10] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA
关键词
DOUBLE-BLIND; CYCLOPHOSPHAMIDE; IPILIMUMAB; RADIOTHERAPY; MULTICENTER; COMBINATION; PLACEBO;
D O I
10.1158/1078-0432.CCR-19-3372
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. Patients and Methods: We conducted a neoadjuvant, randomized study to quantify the immunologic effects of a GM-CSF-secreting allogeneic cellular vaccine in combination with low-dose cydophosphamide (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 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 CHIT1, a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared with 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.
引用
收藏
页码:3182 / 3192
页数:11
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