Anticancer Immunotherapy by MFAP5 Blockade Inhibits Fibrosis and Enhances Chemosensitivity in Ovarian and Pancreatic Cancer

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2019 Jul 24

PMID 31332047

Citations 37

Authors

Tsz-Lun Yeung

Cecilia S Leung

Kay-Pong Yip

Jianting Sheng

Long Vien

Laura C Bover

Michael J Birrer

Stephen T C Wong

Samuel C Mok

Affiliations

Soon will be listed here.

Abstract

Purpose: Recent studies demonstrate the role of the tumor microenvironment in tumor progression. However, strategies used to overcome the malignant phenotypes of cancer cells modulated by the microenvironment have not been thoroughly explored. In this study, we evaluated the therapeutic efficacy of a newly developed mAb targeting microfibril-associated protein 5 (MFAP5), which is secreted predominately by cancer-associated fibroblast (CAF), in ovarian and pancreatic cancer models. MAbs were developed using human MFAP5 recombinant protein as an antigen in mice, and antibodies from hybridoma clones were evaluated for their specificity to human and murine MFAP5. An Octet RED384 system was used to determine the kinetics of binding affinity and the specificity of the antibody clones, which were followed by epitope mapping and functional characterization by assays. The therapeutic efficacy of a lead anti-MFAP5 antibody clone 130A in tumor suppression was evaluated by ovarian tumor- and pancreatic tumor-bearing mouse models.

Results: Three hybridoma clones, which produced antibodies with high affinity and specificity to MFAP5, were selected for functional studies. Antibody clone 130A, which recognizes a common epitope shared between human and murine MFAP5 protein, was further selected for studies. Results showed that clone 130A downregulated MFAP5-induced collagen production in CAFs, suppressed intratumoral microvessel leakiness, and enhanced paclitaxel bioavailability in both ovarian and pancreatic cancer mouse models.

Conclusions: These data suggest that MFAP5 blockade using an immunologic approach inhibits fibrosis, induces tumor vessel normalization, and enhances chemosensitivity in ovarian and pancreatic cancer, and can be used as a novel therapeutic agent.

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References

Oldham R, Dillman R . Monoclonal antibodies in cancer therapy: 25 years of progress. J Clin Oncol. 2008; 26(11):1774-7. DOI: 10.1200/JCO.2007.15.7438. View

Lee M, Gao Z, Peterson B . Synthesis of a Fluorescent Analogue of Paclitaxel That Selectively Binds Microtubules and Sensitively Detects Efflux by P-Glycoprotein. Angew Chem Int Ed Engl. 2017; 56(24):6927-6931. PMC: 5679005. DOI: 10.1002/anie.201703298. View

Barcus C, Keely P, Eliceiri K, Schuler L . Stiff collagen matrices increase tumorigenic prolactin signaling in breast cancer cells. J Biol Chem. 2013; 288(18):12722-32. PMC: 3642318. DOI: 10.1074/jbc.M112.447631. View

Micke P, Ostman A . Tumour-stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy?. Lung Cancer. 2004; 45 Suppl 2:S163-75. DOI: 10.1016/j.lungcan.2004.07.977. View

Tlsty T, Coussens L . Tumor stroma and regulation of cancer development. Annu Rev Pathol. 2007; 1:119-50. DOI: 10.1146/annurev.pathol.1.110304.100224. View

Voo K, Bover L, Harline M, Vien L, Facchinetti V, Arima K . Antibodies targeting human OX40 expand effector T cells and block inducible and natural regulatory T cell function. J Immunol. 2013; 191(7):3641-50. PMC: 3812678. DOI: 10.4049/jimmunol.1202752. View

C Mok S, Bonome T, Vathipadiekal V, Bell A, Johnson M, Wong K . A gene signature predictive for outcome in advanced ovarian cancer identifies a survival factor: microfibril-associated glycoprotein 2. Cancer Cell. 2009; 16(6):521-32. PMC: 3008560. DOI: 10.1016/j.ccr.2009.10.018. View

Uhlen M, Bandrowski A, Carr S, Edwards A, Ellenberg J, Lundberg E . A proposal for validation of antibodies. Nat Methods. 2016; 13(10):823-7. PMC: 10335836. DOI: 10.1038/nmeth.3995. View

Navab R, Strumpf D, Bandarchi B, Zhu C, Pintilie M, Ramnarine V . Prognostic gene-expression signature of carcinoma-associated fibroblasts in non-small cell lung cancer. Proc Natl Acad Sci U S A. 2011; 108(17):7160-5. PMC: 3084093. DOI: 10.1073/pnas.1014506108. View

10.

Shields M, Dangi-Garimella S, Redig A, Munshi H . Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression. Biochem J. 2011; 441(2):541-52. PMC: 8215985. DOI: 10.1042/BJ20111240. View

11.

Tewari K, Sill M, Penson R, Huang H, Ramondetta L, Landrum L . Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet. 2017; 390(10103):1654-1663. PMC: 5714293. DOI: 10.1016/S0140-6736(17)31607-0. View

12.

Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M . Towards a knowledge-based Human Protein Atlas. Nat Biotechnol. 2010; 28(12):1248-50. DOI: 10.1038/nbt1210-1248. View

13.

Postow M, Callahan M, Wolchok J . Immune Checkpoint Blockade in Cancer Therapy. J Clin Oncol. 2015; 33(17):1974-82. PMC: 4980573. DOI: 10.1200/JCO.2014.59.4358. View

14.

Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida A, Ponz-Sarvise M . Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017; 214(3):579-596. PMC: 5339682. DOI: 10.1084/jem.20162024. View

15.

Uhlen M, Bjorling E, Agaton C, Szigyarto C, Amini B, Andersen E . A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteomics. 2005; 4(12):1920-32. DOI: 10.1074/mcp.M500279-MCP200. View

16.

McCarroll J, Naim S, Sharbeen G, Russia N, Lee J, Kavallaris M . Role of pancreatic stellate cells in chemoresistance in pancreatic cancer. Front Physiol. 2014; 5:141. PMC: 3988387. DOI: 10.3389/fphys.2014.00141. View

17.

Hurwitz H . Integrating the anti-VEGF-A humanized monoclonal antibody bevacizumab with chemotherapy in advanced colorectal cancer. Clin Colorectal Cancer. 2004; 4 Suppl 2:S62-8. DOI: 10.3816/ccc.2004.s.010. View

18.

Cox T, Erler J . Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech. 2011; 4(2):165-78. PMC: 3046088. DOI: 10.1242/dmm.004077. View

19.

Leung C, Yeung T, Yip K, Pradeep S, Balasubramanian L, Liu J . Calcium-dependent FAK/CREB/TNNC1 signalling mediates the effect of stromal MFAP5 on ovarian cancer metastatic potential. Nat Commun. 2014; 5:5092. PMC: 4185407. DOI: 10.1038/ncomms6092. View

20.

Yeung T, Leung C, Yip K, Yeung C, Wong S, C Mok S . Cellular and molecular processes in ovarian cancer metastasis. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis. Am J Physiol Cell Physiol. 2015; 309(7):C444-56. PMC: 4593771. DOI: 10.1152/ajpcell.00188.2015. View