Skip to main content

Advertisement

SpringerLink
Log in

Docetaxel enhances the therapeutic efficacy of PSMA-specific CAR-T cells against prostate cancer models by suppressing MDSCs

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Prostate cancer can undergo curative effects by radical prostatectomy or radical radiotherapy. However, the best treatment for more aggressive high-risk prostate cancer remains controversial. Insufficient infiltration capacity and dysfunction are commonly occurrences in engineered T lymphocytes expressing chimeric antigen receptor (CAR-T), characterizing cancer immunotherapy failure. We conducted this study to investigate whether the combinative application of docetaxel and PSMA-CAR-T cells could be a more effective treatment to prostate cancer.

Methods

Expressions of prostate specific membrane antigen (PSMA) on prostate cancer cells were examined by Flow cytometry. The efficaciousness of PSMA-CAR-T was evaluated in vitro using ELISA and RTCA. The effect of intermixed therapy was assessed in vivo utilizing a human prostate cancer liver metastasis mouse model and a human prostate cancer cell xenograft mouse model.

Results

The outcome of cytokine discharge and cell killing assays demonstrated that PSMA-CAR-T cells have characteristic effector capacity against PSMA+ prostate cancer cells in vitro. Additionally, collaborative treatment of PSMA-CAR-T cells and docetaxel have cooperative efficacy in a mouse model of human prostate cancer. The merged strategy could be seen as an undeveloped avenue to augmenting adoptive CAR-T cell immunotherapy and mitigating the adverse side effects of chemotherapy.

Conclusions

Cooperation of PSMA-specific CAR-T cells and the chemotherapy drug docetaxel can impressively ameliorate antitumor effectiveness against an installed metastatic human prostate cancer model in NPG mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

All data are available in the main text or the supplementary materials.

Abbreviations

ADT:

Androgen replacement therapy

CAR-T:

Chimeric antigen receptor T cell

CRPC:

Castration-resistant prostate cancer

DTX:

Docetaxel

HMGB1:

High mobility group protein B1

PSMA:

Prostate specific membrane antigen

MDSCs:

Myeloid-derived suppressor cells

TAMs:

Tumor-associated macrophages

Tregs:

Regulatory T cells

RTCA:

Real time cell analysis

ELISA:

Enzyme linked immunosorbent assay

References

  • Achkova D, Pule M (2018) CAR T-cell integration of multiple input signals allows for precise targeting of cancer. Cancer Discov 8:918–920

    Article  CAS  Google Scholar 

  • Beltran H, Morris M (2020) Docetaxel for early prostate cancer: what have we learned? Eur Urol 77:573–575

    Article  CAS  Google Scholar 

  • D’Aloia MM, Zizzari IG, Sacchetti B, Pierelli L, Alimandi M (2018) CAR-T cells: the long and winding road to solid tumors. Cell Death Dis 9:282

    Article  Google Scholar 

  • da Costa R, Passos G, Quintão N, Fernandes E, Maia J, Campos M, Calixto J (2020) Taxane-induced neurotoxicity: pathophysiology and therapeutic perspectives. Br J Pharmacol 177:3127–3146

    Article  Google Scholar 

  • Djeu J, Wei S (2012) Chemoimmunomodulation of MDSCs as a novel strategy for cancer therapy. Oncoimmunology 1:121–122

    Article  Google Scholar 

  • Gao Q, Wang S, Chen X, Cheng S, Zhang Z, Li F, Huang L, Yang Y, Zhou B, Yue D, Wang D, Cao L, Maimela N, Zhang B, Yu J, Wang L, Zhang Y (2019) Cancer-cell-secreted CXCL11 promoted CD8 T cells infiltration through docetaxel-induced-release of HMGB1 in NSCLC. J Immunother Cancer 7:42

    Article  Google Scholar 

  • Gorchakov AA, Kulemzin SV, Kochneva GV, Taranin AV (2019) Challenges and prospects of chimeric antigen receptor T-cell therapy for metastatic prostate cancer. Eur Urol 77:299

    Article  Google Scholar 

  • Hu Y, Liu J, Cui P, Liu T, Piao C, Xu X, Zhang Q, Xiao M, Lu Y, Liu X, Wang Y, Lu X (2020) Synergistic effect of adoptive immunotherapy and docetaxel inhibits tumor growth in a mouse model. Cell Immunol 348:104036

    Article  CAS  Google Scholar 

  • Kodumudi K, Woan K, Gilvary D, Sahakian E, Wei S, Djeu J (2010) A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res 16:4583–4594

    Article  CAS  Google Scholar 

  • Nabholtz J, Gligorov J (2005) Docetaxel in the treatment of breast cancer: current experience and future prospects. Expert Rev Anticancer Ther 5:613–633

    Article  CAS  Google Scholar 

  • Porter DL, Levine BL, Kalos M, Bagg A, June CH (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365:725–733

    Article  CAS  Google Scholar 

  • Rafiq S, Hackett C, Brentjens R (2020) Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol 17:147–167

    Article  Google Scholar 

  • Rochigneux P, Schleinitz N, Ebbo M, Aymonier M, Pourroy B, Boissier R, Salas S, Deville J (2018) Acute myositis: an unusual and severe side effect of docetaxel: a case report and literature review. Anticancer Drugs 29:477–481

    Article  CAS  Google Scholar 

  • Siegel D, O’Neil M, Richards T, Dowling N, Weir H (2020) Prostate cancer incidence and survival, by stage and race/ethnicity - united states, 2001–2017. MMWR Morb Mortal Wkly Rep 69:1473–1480

    Article  Google Scholar 

  • Siegel R, Miller K, Fuchs H, Jemal A (2021) Cancer statistics 2021. CA Cancer J Clin 71:7–33

    Article  Google Scholar 

  • Verma A, Warner SL, Vankayalapati H, Bearss DJ, Sharma S (2011) Targeting Axl and Mer kinases in cancer. Mol Cancer Ther 10:1763–1773

    Article  CAS  Google Scholar 

  • Wen X, Zheng P, Ma Y, Ou Y, Huang W, Li S, Liu S, Zhang X, Wang Z, Zhang Q, Cheng W, Lin R, Li H, Cai Y, Hu C, Wu N, Wan L, Pan T, Rao J, Bei X, Wu W, Jin J, Yan J, Liu G (2018) Salutaxel, a conjugate of docetaxel and a muramyl dipeptide (MDP) analogue, acts as multifunctional prodrug that inhibits tumor growth and metastasis. J Med Chem 61:1519–1540

    Article  CAS  Google Scholar 

  • Xu J, Tian K, Zhang H, Li L, Liu H, Liu J, Zhang Q, Zheng J (2017) Chimeric antigen receptor-T cell therapy for solid tumors require new clinical regimens. Expert Rev Anticancer Ther 17:1099–1106

    Article  CAS  Google Scholar 

  • Xuan L, Sun B, Meng X, Liu C, Cong Y, Wu S (2020) Ototoxicity in patients with invasive ductal breast cancer who were treated with docetaxel: report of two cases. Cancer Biol Ther 21:990–993

    Article  CAS  Google Scholar 

  • Zhao J, Lin Q, Song Y, Liu D (2018) Universal CARs, universal T cells, and universal CAR T cells. J Hematol Oncol 11:132

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by grants from the National Science Foundation of China (81773253, 81972242), Natural Science Foundation of Jiangsu Province (BK20211057), the Youth Technology Innovation Team of Xuzhou Medical University (TD202003), the Jiangsu Provincial Key Medical Discipline, and the Project of Invigorating Health Care through Science, Technology and Education (ZDXKA2016014), the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (19KJB310001, 19KJB310018, 18KJA320013), the Natural Science Key Project of Jiangsu Provincial Education Department (20KJA320006), Six talent peaks project in Jiangsu Province (WSW-064), Xuzhou Science and Technology Bureau projects grant (KC19058), the Research Foundation of Xuzhou Medical University (D2019023), the Qing Lan Project of Jiangsu Province to XG.

Author information

Author notes

  1. Xiaokang Zhang, Shishuo Sun and Yangna Miao these authors are contributed equally to this work.

Authors and Affiliations

  1. Cancer Institute, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, People’s Republic of China

    Xiaokang Zhang, Shishuo Sun, Yangna Miao, Yifan Yuan, Wanxin Zhao, Hailong Li, Xiaohuan Wei, Chao Huang, Xiaolei Hu, Bixi Wang, Heng Xu, Wei Zhang, Xiaoge Gao, Jingyuan Song, Junnian Zheng & Qing Zhang

  2. Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China

    Xiaokang Zhang, Shishuo Sun, Yangna Miao, Yifan Yuan, Wanxin Zhao, Xiaohuan Wei, Chao Huang, Xiaolei Hu, Bixi Wang, Heng Xu, Wei Zhang, Xiaoge Gao, Junnian Zheng & Qing Zhang

  3. Department of Urology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China

    Hailong Li

  4. School of Nursing, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China

    Jingyuan Song

  5. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China

    Shishuo Sun, Xiaoge Gao & Qing Zhang

Authors
  1. Xiaokang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shishuo Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yangna Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yifan Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wanxin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hailong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiaohuan Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaolei Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bixi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Heng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Xiaoge Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jingyuan Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Junnian Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Qing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, JZ and QZ; methodology, XG, JS; software, HL; validation, XZ, SS, and YM; formal analysis, YY, WZ; investigation, XZ, SS, YM, XW, CH and XH; resources, QZ and JZ; data curation, XZ, and BW; writing—original draft preparation, XZ; writing—review and editing, SS, and QZ; visualization, HX, WZ; supervision, JZ and QZ; project administration, JZ and QZ; funding acquisition, HL, SS, XG, JS, JZ and QZ. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Junnian Zheng or Qing Zhang.

Ethics declarations

Conflict of interests

All authors have declared that there are no financial conflicts of interest with regard to this work.

Compliance with ethical standards

All procedures performed in studies involving human samples were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent to publish

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 136 KB) Supplementary Fig. 1

Ex Vivo Docetaxel Existing Does Not Notably Spoil Expanding and Killing Capacity of PSMA-CAR-T Cells. A, Influence of docetaxel on the expanding of PSMA-CAR-T cells by cell counting. B, Influence of docetaxel on the cytokine release of PSMA-CAR-T cells by ELISA. C, Influence of docetaxel on the cytotoxic capacity of PSMA-CAR-T cells. PSMA-CAR-T cells were pretreated with docetaxel for 48 hours. *P<0.05; ns, not significant.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, X., Sun, S., Miao, Y. et al. Docetaxel enhances the therapeutic efficacy of PSMA-specific CAR-T cells against prostate cancer models by suppressing MDSCs. J Cancer Res Clin Oncol 148, 3511–3520 (2022). https://doi.org/10.1007/s00432-022-04248-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-022-04248-y

Keywords

Search

Navigation