Myeloid derived suppressor and dendritic cell subsets are related to clinical outcome in prostate cancer patients treated with prostate GVAX and ipilimumab

Journal for ImmunoTherapy of Cancer

Tanja D de Gruijl¹  Alfons JM van den Eertwegh¹  Winald R Gerritsen¹  Rik J Scheper²  Israel Lowy⁴  Kristen Hege³  Natalie Sacks³  Karin Jooss³  Helen Gall¹  Sinéad M Lougheed¹  Anita GM Stam²  Saskia JAM Santegoets¹ 

[1] Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands;Department of Pathology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands;Cell Genesys Inc, South San Francisco, CA, USA;Medarex, Bloomsbury, NJ/Bristol-Myers Squibb Company, Wallingford, CT, USA

关键词: Survival prediction;    Patient selection;    Biomarker;    Prostate GVAX;    Ipilimumab;   

Others  :  1139870
DOI  :  10.1186/s40425-014-0031-3

 received in 2014-04-09, accepted in 2014-08-06,  发布年份 2014

【 摘 要 】

Background

Cancer-related disturbances in myeloid lineage development, marked by high levels of myeloid-derived suppressor cells (MDSC) and impaired dendritic cell (DC) development, are associated with poor clinical outcome due to immune escape and therapy resistance. Redressing this balance may therefore be of clinical benefit. Here we investigated the effects of combined Prostate GVAX/ipilimumab immunotherapy on myeloid subsets in peripheral blood of castration-resistant prostate cancer (CRPC) patients as well as the putative predictive value of baseline and on-treatment myeloid parameters on clinical outcome.

Methods

Patients with CRPC (n?=?28) received thirteen intradermal administrations of Prostate GVAX, consisting of two allogeneic GM-CSF-transduced and irradiated prostate cancer cell lines (LN-CaP and PC3) and six infusions of escalating doses of anti-CTLA4/ipilimumab. Frequencies and activation status of peripheral blood DC (PBDC) and MDSC were determined before, during and after treatment by flowcytometric analysis and related to clinical benefit.

Results

Significant treatment-induced activation of conventional and plasmacytoid DC subsets (cDC and pDC) was observed, which in the case of BDCA1/CD1c⁺ cDC1 and MDC8⁺/6-sulfoLacNAc⁺ inflammatory cDC3 was associated with significantly prolonged overall survival (OS), but also with the development of autoimmune-related adverse events. High pre-treatment levels of CD14⁺HLA-DR^?monocytic MDSC (mMDSC) were associated with reduced OS. Unsupervised clustering of these myeloid biomarkers revealed particular survival advantage in a group of patients with high treatment-induced PBDC activation and low pretreatment frequencies of suppressive mMDSC in conjunction with our previously identified lymphoid biomarker of high pretreatment CD4⁺CTLA4⁺ T cell frequencies.

Conclusions

Our data demonstrate that DC and MDSC subsets are affected by prostate GVAX/ipilimumab therapy and that myeloid profiling may contribute to the identification of patients with possible clinical benefit of Prostate GVAX/ipilimumab treatment.

【 授权许可】

   
2014 Santegoets et al.; licensee BioMed Central Ltd.

【 图 表 】

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