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Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

PD-1 blockade in combination with zoledronic acid to enhance the antitumor efficacy in the breast cancer mouse model

Authors: Yuan Li, Yang Du, Ting Sun, Huadan Xue, Zhengyu Jin, Jie Tian

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

Blockade of PD-1 receptor may provide proof of concepts for the activity of an immune-modulation approach for the treatment of breast cancer (BC). Zoledronic acid (ZA) has been proven to inhibit angiogenesis, invasion, and adhesion of tumor cells. The aim of this study was to investigate the potential of monoclonal antibody against T cell checkpoint PD-1 in combination with chemotherapeutic drug ZA in BC mouse model.

Methods

The 4 T1-fLuc mouse BC model was used in this study. The anti-tumor efficacy of anti-PD-1 antibody alone or in combination with ZA was monitored by measuring bioluminescence imaging (BLI) and tumor volume. At the end of study, the flow cytometry was used to determine the immune cell population in tumors after different treatment.

Results

The results showed that mice treated with the combination therapy of anti-PD-1 antibody plus ZA exhibited better antitumor response compared to untreated controls or single therapy with no obvious toxicity.

Conclusion

Our study provides preclinical evidence for the enhanced BC treatment benefit through targeting co-signal molecules by combining anti-PD-1 antibody plus ZA treatment.
Literature
1.
go back to reference Maccio A, Madeddu C, Mantovani G. Adipose tissue as target organ in the treatment of hormone-dependent breast cancer: new therapeutic perspectives [J]. Obes Rev. 2009;10(6):660–70.CrossRefPubMed Maccio A, Madeddu C, Mantovani G. Adipose tissue as target organ in the treatment of hormone-dependent breast cancer: new therapeutic perspectives [J]. Obes Rev. 2009;10(6):660–70.CrossRefPubMed
2.
go back to reference Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012[J]. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMed Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012[J]. CA Cancer J Clin. 2015;65(2):87–108.CrossRefPubMed
3.
go back to reference Su M, Huang CX, Dai AP. Immune checkpoint inhibitors: therapeutic tools for breast Cancer[J]. Asian Pac J Cancer Prev. 2016;17(3):905–10.CrossRefPubMed Su M, Huang CX, Dai AP. Immune checkpoint inhibitors: therapeutic tools for breast Cancer[J]. Asian Pac J Cancer Prev. 2016;17(3):905–10.CrossRefPubMed
4.
go back to reference Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer[J]. N Engl J Med. 2012;366(26):2455–65.CrossRefPubMedPubMedCentral Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer[J]. N Engl J Med. 2012;366(26):2455–65.CrossRefPubMedPubMedCentral
5.
6.
go back to reference Bedognetti D, Maccalli C, Bader SB, et al. Checkpoint inhibitors and their application in breast Cancer[J]. Breast Care (Basel). 2016;11(2):108–15.CrossRef Bedognetti D, Maccalli C, Bader SB, et al. Checkpoint inhibitors and their application in breast Cancer[J]. Breast Care (Basel). 2016;11(2):108–15.CrossRef
7.
go back to reference Migali C, Milano M, Trapani D, et al. Strategies to modulate the immune system in breast cancer: checkpoint inhibitors and beyond[J]. Ther Adv Med Oncol. 2016;8(5):360–74.CrossRefPubMedPubMedCentral Migali C, Milano M, Trapani D, et al. Strategies to modulate the immune system in breast cancer: checkpoint inhibitors and beyond[J]. Ther Adv Med Oncol. 2016;8(5):360–74.CrossRefPubMedPubMedCentral
8.
go back to reference Nivolumab Doubles Survival for Patients with HNSCC[J]. Cancer Discov. 2016;6(7):F3.CrossRef Nivolumab Doubles Survival for Patients with HNSCC[J]. Cancer Discov. 2016;6(7):F3.CrossRef
9.
go back to reference Mann JE, Hoesli R, Michmerhuizen NL, et al. Surveilling the potential for precision medicine-driven PD-1/PD-L1-targeted therapy in HNSCC[J]. J Cancer. 2017;8(3):332–44.CrossRefPubMedPubMedCentral Mann JE, Hoesli R, Michmerhuizen NL, et al. Surveilling the potential for precision medicine-driven PD-1/PD-L1-targeted therapy in HNSCC[J]. J Cancer. 2017;8(3):332–44.CrossRefPubMedPubMedCentral
10.
go back to reference Melani C, Sangaletti S, Barazzetta FM, et al. Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma[J]. Cancer Res. 2007;67(23):11438–46.CrossRefPubMedPubMedCentral Melani C, Sangaletti S, Barazzetta FM, et al. Amino-biphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stroma[J]. Cancer Res. 2007;67(23):11438–46.CrossRefPubMedPubMedCentral
11.
go back to reference Yamada J, Tsuno NH, Kitayama J, et al. Anti-angiogenic property of zoledronic acid by inhibition of endothelial progenitor cell differentiation[J]. J Surg Res. 2009;151(1):115–20.CrossRefPubMed Yamada J, Tsuno NH, Kitayama J, et al. Anti-angiogenic property of zoledronic acid by inhibition of endothelial progenitor cell differentiation[J]. J Surg Res. 2009;151(1):115–20.CrossRefPubMed
12.
go back to reference Coscia M, Quaglino E, Iezzi M, et al. Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway[J]. J Cell Mol Med. 2010;14(12):2803–15.CrossRefPubMed Coscia M, Quaglino E, Iezzi M, et al. Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway[J]. J Cell Mol Med. 2010;14(12):2803–15.CrossRefPubMed
13.
go back to reference Comito G, Segura CP, Taddei ML, et al. Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts[J]. Oncotarget. 2016; Comito G, Segura CP, Taddei ML, et al. Zoledronic acid impairs stromal reactivity by inhibiting M2-macrophages polarization and prostate cancer-associated fibroblasts[J]. Oncotarget. 2016;
14.
go back to reference Barrett-Lee P, Casbard A, Abraham J, et al. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial[J]. Lancet Oncol. 2014;15(1):114–22.CrossRefPubMed Barrett-Lee P, Casbard A, Abraham J, et al. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial[J]. Lancet Oncol. 2014;15(1):114–22.CrossRefPubMed
15.
go back to reference Coleman R, Cameron D, Dodwell D, et al. Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial[J]. Lancet Oncol. 2014;15(9):997–1006.CrossRefPubMed Coleman R, Cameron D, Dodwell D, et al. Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial[J]. Lancet Oncol. 2014;15(9):997–1006.CrossRefPubMed
16.
go back to reference Jia XH, Du Y, Mao D, et al. Zoledronic acid prevents the tumor-promoting effects of mesenchymal stem cells via MCP-1 dependent recruitment of macrophages[J]. Oncotarget. 2015;6(28):26018–28.CrossRefPubMedPubMedCentral Jia XH, Du Y, Mao D, et al. Zoledronic acid prevents the tumor-promoting effects of mesenchymal stem cells via MCP-1 dependent recruitment of macrophages[J]. Oncotarget. 2015;6(28):26018–28.CrossRefPubMedPubMedCentral
17.
go back to reference Wang L, Su W, Liu Z, et al. CD44 antibody-targeted liposomal nanoparticles for molecular imaging and therapy of hepatocellular carcinoma[J]. Biomaterials. 2012;33(20):5107–14.CrossRefPubMed Wang L, Su W, Liu Z, et al. CD44 antibody-targeted liposomal nanoparticles for molecular imaging and therapy of hepatocellular carcinoma[J]. Biomaterials. 2012;33(20):5107–14.CrossRefPubMed
18.
go back to reference Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation[J]. Nat Immunol. 2001;2(3):261–8.CrossRefPubMed Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation[J]. Nat Immunol. 2001;2(3):261–8.CrossRefPubMed
19.
go back to reference Kitazawa Y, Fujino M, Wang Q, et al. Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+CD25+ regulatory T-cell activity to suppress alloimmune responses[J]. Transplantation. 2007;83(6):774–82.CrossRefPubMed Kitazawa Y, Fujino M, Wang Q, et al. Involvement of the programmed death-1/programmed death-1 ligand pathway in CD4+CD25+ regulatory T-cell activity to suppress alloimmune responses[J]. Transplantation. 2007;83(6):774–82.CrossRefPubMed
20.
go back to reference Ren HT, Li YM, Wang XJ, et al. PD-1 rs2227982 polymorphism is associated with the decreased risk of breast Cancer in northwest Chinese women: a hospital-based observational study[J]. Medicine (Baltimore). 2016;95(21):e3760.CrossRef Ren HT, Li YM, Wang XJ, et al. PD-1 rs2227982 polymorphism is associated with the decreased risk of breast Cancer in northwest Chinese women: a hospital-based observational study[J]. Medicine (Baltimore). 2016;95(21):e3760.CrossRef
21.
go back to reference Kanda S, Goto K, Shiraishi H, et al. Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study[J]. Ann Oncol. 2016;27(12):2242–50.CrossRefPubMedPubMedCentral Kanda S, Goto K, Shiraishi H, et al. Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study[J]. Ann Oncol. 2016;27(12):2242–50.CrossRefPubMedPubMedCentral
22.
go back to reference Iwai Y, Hemmi H, Mizenina O, Kuroda S, Suda K, Steinman RM. An IFN-gamma-IL-18 signaling loop accelerates memory CD8+ T cell proliferation. PLoS One. 2008;3(6):e2404.CrossRefPubMedPubMedCentral Iwai Y, Hemmi H, Mizenina O, Kuroda S, Suda K, Steinman RM. An IFN-gamma-IL-18 signaling loop accelerates memory CD8+ T cell proliferation. PLoS One. 2008;3(6):e2404.CrossRefPubMedPubMedCentral
23.
go back to reference Kuroda J, Kimura S, Segawa H, et al. The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate[J]. Blood. 2003;102(6):2229–35.CrossRefPubMed Kuroda J, Kimura S, Segawa H, et al. The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate[J]. Blood. 2003;102(6):2229–35.CrossRefPubMed
24.
go back to reference Hiraga T, Williams PJ, Ueda A, et al. Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model[J]. Clin Cancer Res. 2004;10(13):4559–67.CrossRefPubMed Hiraga T, Williams PJ, Ueda A, et al. Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model[J]. Clin Cancer Res. 2004;10(13):4559–67.CrossRefPubMed
Metadata
Title
PD-1 blockade in combination with zoledronic acid to enhance the antitumor efficacy in the breast cancer mouse model
Authors
Yuan Li
Yang Du
Ting Sun
Huadan Xue
Zhengyu Jin
Jie Tian
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4412-8

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