Anti-S100A4 antibody therapy is efficient in treating aggressive prostate cancer and reversing immunosuppression: Serum and biopsy S100A4 as clinical predictor.

S100A4 oncoprotein plays a critical role during prostate cancer (CaP) progression and induces immunosuppression in host-tissues. We hypothesized that S100A4 activity in immunosuppressed prostate tumors promotes the growth of neoplastic cells which are likely to become aggressive. In the current study, we investigated if biopsy-S100A4 gene alteration independently predicts the outcome of disease in patients and circulatory-S100A4 is druggable target for treating immunosuppressive-CaP. Aided by DECIPHER-genomic test, we show biopsy-S100A4 overexpression as predictive of (i) poor ADT-response and (ii) high-risk of mortality in 228 radical prostatectomy-treated patients. Furthermore, analysis of tumor genome data of >1000 CaP patients (PRAD/SU2C/FHCRC studies) validated the association of S100A4-alteration to poor-survival and metastasis. We show that increased serum-S100A4 levels are associated to the CaP progression in patients. The prerequisite for metastasis is the escape of tumor cells via vascular system. We show that extracellular-S100A4 protein as a growth factor induces vascular transmigration of CaP cells and bone-mineralization thus forms an ideal target for therapies for treating CaP. By employing Surface-Plasmon-resonance and ITC, we show that mab6B12 antibody interacts with and neutralizes S100A4 protein. When tested for therapeutic efficacy, the mab6B12 antibody-therapy reduced (i) osteoblastic mineralization of bone-derived MSC`s, (ii) S100A4-targets (NFkB/MMP9/VEGF) in CaP-cells, and (iii) TRAMPC2-cell tumorigenicity in an immunosufficient mouse model. The immuno-profile analysis showed that mAb6B12-therapy (i) shifted Th1/Th2 balance (increased-Stat4+/T-bet+, & decreased-GATA2+/CD68+/CD45+/CD206+ cells), (ii) modulated cytokine-levels in CD4+ve T-cells, and (iii) decreased levels of Interleukin-5/6/12/13, sTNFR1 and serum-RANTES. We suggest that S100A4-antibody therapy has clinical applicability in treating immunosuppressive- CaP in patients.