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CD200 mimetic aptamer PEG-M49 markedly increases the therapeutic effects of pegylated liposomal doxorubicin in a mouse model of metastatic breast carcinoma: an effect independent of CD200 receptor 1

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Abstract

We previously reported that CD200 overexpression in the host decreases progression and metastasis of the highly aggressive metastatic 4THM breast carcinoma. We have explored a possible synergistic interaction between the CD200 mimetic PEG-M49 and pegylated liposomal doxorubicin (Peg-Dox) in wild-type CD200 knockout (CD200−/−) and CD200 Receptor 1 knockout (CD200R1−/−) mice for the first time. A 4THM breast carcinoma model and three groups of BALB/c mice (wild type, CD200−/− and CD200R1−/−) were used. Five days after injection of tumor cells, mice were injected with Peg-Dox (ip, once a week) and PEG-M49 or a control aptamer (iv, every 3 days). Necropsies were performed either 12 (mid-point) or 24 (endpoint) days after injection and the extent of tumor growth, visceral metastasis and changes in the tumor-directed immune response were evaluated. PEG-M49 and Peg-Dox co-treatment induced complete tumor regression and loss of macroscopic lung metastasis in four out of seven WT mice. This synergistic anti-tumoral effect is thought to be due to Peg-M49-induced inhibition of Gr1 + CD11b + cells and Peg-Dox-induced increases in tumor-infiltrating CD8 + and CD8CD4 double-positive cells. Similar changes were observed in CD200R1−/− mice indicating that the primary effects of Peg-M49 are mediated by non-CD200R1 receptors. We also demonstrated for the first time that tumor growth, metastasis, and tumor infiltrating GR1 + CD11b + cells were markedly increased in CD200R1−/− mice, indicating an anti-inflammatory and protective role of CD200. CD200 mimetics might be a safe and effective immunomodulatory treatment in conjunction with classical chemotherapeutics for therapy of aggressive metastatic breast carcinoma.

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Abbreviations

Apt:

Control aptamer

CD200−/− :

CD200 knockout mice

CD200R1:

CD200 receptor 1

CD200R1−/− :

CD200R1 knockout mice

DLN:

Draining lymph nodes

KATP:

ATP-sensitive potassium

LCs:

Leucocyte culture

Peg-Dox:

Pegylated liposomal doxorubicin

Peg-M49:

Pegylated conjugates of M49

UHN:

University Health Network in Toronto

WT:

Wild type

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Funding

This work was supported by funds from Akdeniz University Research Units, Antalya, Turkey (Project no: TUA-2015-585); and from the Canadian Cancer Society (Grant to Reginald M. Gorczynski).

Author information

Authors and Affiliations

  1. Department of Medical Pharmacology, Immunopharmacology and Immunooncology Research unit, Akdeniz University School of Medicine, B-Blok Kat 1 Immunoloji, 07070, Antalya, Turkey

    Nuray Erin & Özlem Duymuş

  2. Department of Histology and Embryology, Akdeniz University School of Medicine, Antalya, Turkey

    Sayra Dilmaç & Gamze Tanriover

  3. University Health Network, Toronto General Hospital, Toronto, Canada

    Anna Curry & Reginald M. Gorczynski

  4. Sunnybrook Cancer Centre, Toronto General Hospital, Toronto, Canada

    Aaron Prodeus & Jean Gariepy

Authors
  1. Nuray Erin
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  2. Sayra Dilmaç
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  8. Reginald M. Gorczynski
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Contributions

NE planned and performed the experiments, and was involved in analysis of the results and writing of the manuscript; SD and GT performed histological studies and microscopic determination of metastasis as well as writing the related parts of the manuscript; AC participated in animal experiments and flow cytometry studies; ÖD determined the changes in cytokine levels and analyzed the results. JG and AP designed and provided Peg-M49; RMG planned and performed the experiments on animals, as well as participated in writing of the manuscript.

Corresponding author

Correspondence to Nuray Erin.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

Ethical approval from the Toronto University Health Network (UHN) ethics committee, supervising studies involving animals, was given to Reginald M. Gorczynski (Protocol no. AUP1.15). All animal experimentations were performed following the guidelines of an accredited animal care committee (Toronto General Hospital Animal Care Committee, UHN).

Animal source

Wild-type (WT) female BALB/c mice were purchased from the Jackson Laboratories, Bar Harbor, ME.

Cell line authentication

The 4THM cell line, established by Nuray Erin, was derived from heart metastasis of the 4T1 cells. The 4THM cell line, kept in liquid nitrogen, forms primary tumors when injected into the mammary pad of BALB/c mice even after 50 passages.

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Erin, N., Dilmaç, S., Curry, A. et al. CD200 mimetic aptamer PEG-M49 markedly increases the therapeutic effects of pegylated liposomal doxorubicin in a mouse model of metastatic breast carcinoma: an effect independent of CD200 receptor 1. Cancer Immunol Immunother 69, 103–114 (2020). https://doi.org/10.1007/s00262-019-02444-3

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