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

Arsheed A Ganaie, Adrian Mansini, Tabish Hussain, Arpit Rao, Hifzur R. Siddique, Ashraf Shabaneh, Marina G Ferrari, Paari Murugan, Jorg Klingelhofer, Jinhua Wang, Noona Ambartsumian, Christopher A Warlick, Badrinath R Konety, Mohammad Saleem

Research output: Contribution to journalArticlepeer-review

Abstract

S100A4 oncoprotein plays a critical role during prostate cancer progression and induces immunosuppression in host tissues. We hypothesized that S100A4-regulated oncogenic activity in immunosuppressed prostate tumors promotes growth of neoplastic cells, which are likely to become aggressive. In the current study, we investigated whether biopsy-S100A4 gene alteration independently predicts the outcome of disease in patients and circulatory-S100A4 is druggable target for treating immunosuppressive prostate cancer. Aided by DECIPHER-genomic test, we show biopsy-S100A4 over-expression 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 more than 1,000 patients with prostate cancer (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 prostate cancer 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 prostate cancer cells and bone demineralization thus forms an ideal target for therapies for treating prostate cancer. By employing surface plasmon resonance and isothermal titration calorimetry, we show that mab6B12 antibody interacts with and neutralizes S100A4 protein. When tested for therapeutic efficacy, the mab6B12 therapy reduced the (i) osteoblastic demineralization of bone-derived MSCs, (ii) S100A4-target (NFkB/MMP9/VEGF) levels in prostate cancer cells, and (iii) tumor growth in a TRAMPC2 syngeneic mouse model. The immuno-profile analysis showed that mAb6B12-therapy (i) shifted Th1/Th2 balance (increased Stat4þ/T-betþ and decreased GATA2þ/CD68þ/CD45þ/CD206þ cells); (ii) modulated cytokine levels in CD4þ T cells; and (iii) decreased levels of IL5/6/12/13, sTNFR1, and serum-RANTES. We suggest that S100A4-antibody therapy has clinical applicability in treating immunosuppressive prostate cancer in patients.

Original languageEnglish (US)
Pages (from-to)2598-2611
Number of pages14
JournalMolecular Cancer Therapeutics
Volume19
Issue number12
DOIs
StatePublished - Dec 1 2020

Bibliographical note

Funding Information:
This study was supported by an R01 grant from US PHS/NIH (CA193739) to M. Saleem. The research activity of M. Saleem was also supported by US

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

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