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Tumor-associated macrophages (TAMs) modulate response to HER2-targeted agents in a humanized mouse model of breast cancer

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Abstract

Purpose

Tumor-associated macrophages (TAM) may participate to antitumor activity of anti-HER2-targeted therapies (Pertuzumab, Trastuzumab) in breast cancers harbouring HER-2 overexpression through antibody-dependent phagocytosis. Additive antitumor effect of concurrent cytotoxic chemotherapies, including Paclitaxel, may be counterbalanced by alteration in TAM infiltrate. The aim of this study is to evaluate the role of TAM in tumor response to anti-HER2-targeted therapies and chemotherapy in an experimental model of HER2-amplified breast cancer.

Methods

A xenograft mouse model was built by subcutaneous injection of the SKBR-3 human HER2-amplified breast cancer cell line in Hu-CD34+ mice. Animals were randomized to receive weekly administration of Cremophor (control), Trastuzumab+Pertuzumab (TP), and Paclitaxel+Trastuzumab+Pertuzumab (PTP) with or without macrophage depletion with clodronate (C). At week 4, mice were euthanised and tumors were harvested for immunohistochemical analysis of TAM infiltration (RBP-J CD163 and CD68 for M1, M2, and overall TAM, respectively).

Results

Tumor size was significantly lower in mice treated with TP, PTP, and PTP+C as compared to control, while no meaningful difference was observed in the TP+C arm. Analysis of TAM infiltrate showed significantly lower CD68 and CD163 expression in PTP, TP+C, and PTP+C as compared to TP and control arm. RBP-J expression was significantly decreased in mice treated with clodronate depletion.

Conclusions

Activity of TP is modulated by TAM infiltrate, that is inhibited by concurrent administration of Paclitaxel. To enhance the effect of anti-HER2-targeted therapies and minimize chemotherapy-related side effects, modulation of TAM should be considered in novel therapeutic combinations.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

ADCC:

Antibody Dependent Cell Cytotoxicity

ADCP:

Antibody-dependent cellular phagocytosis

C:

Clodronate

HLA:

Human leukocyte antigen

hu-CD34:

Human CD34 + hematopoietic stem cells

NK:

Natural Killer

null:

NOD-SCID IL2rgamma

PTP:

Paclitaxel combined with trastuzumab and pertuzumab

TP:

Trastuzumab with pertuzumab

TILs:

T-lymphocytes

TAMs:

Tumor-associated macrophages

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Acknowledgements

This is an investigator-initiated study designed by our research unit. The study sponsor is University of Florence, Italy. The study drugs were provided by Genentech via material transfer agreement. Partial financial support for the conduct of the research was provided by Roche, who had no role in study design and in the preparation of this article. It also had no role in the collection, analysis and interpretation of the data as in the writing of the final manuscript. Funding is also ensured by the study sponsor and by a no-profit charity organization (Fondazione Radioterapia Oncologica, FRO). All authors have read the journal’s authorship agreement and reviewed the manuscript. The authors have read the journal’s policy on disclosure of potential conflicts of interest and declare no conflicts of interest.

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Authors and Affiliations

  1. Radiotherapy Department, University of Florence, 3, Largo Brambilla, 50124, Florence, Italy

    M. Loi, G. Salvatore, M. Sottili, I. Desideri, C. Becherini, V. Salvestrini, L. P. Ciccone, G. Stocchi, I. Meattini, G. Francolini, M. Mangoni & L. Livi

  2. Department of Biomedical and Experimental Sciences, University of Florence, Florence, Italy

    I. Desideri, I. Meattini, M. Mangoni & L. Livi

  3. Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, Research Unit of Histology an Embryology, University of Florence, Florence, Italy

    L. Calosi

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Contributions

ML: conceptualization; data curation; investigation; methodology; writing—original draft. GS: data curation; formal analysis; investigation; methodology; software; writing—original draft; MS: investigation; methodology; validation; visualization; writing—review and editing. LC: investigation; data curation; writing—original draft. CB: investigation; data curation; writing—original draft. VS: investigation; data curation; writing—original draft. LPC: investigation; methodology; validation; visualization; writing—review and editing. GS: investigation; methodology; validation; visualization; writing—review and editing. GF: investigation; data curation; writing—original draft. ID: investigation; data curation; writing—original draft. IM: writing—review and editing. MM: supervision; investigation; methodology; validation; visualization; writing—review and editing. LL: investigation; methodology; validation; visualization; writing—review and editing. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to M. Loi.

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The authors declare no competing interests.

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In vivo experiments were performed in accordance with Directive 2010/63/EU on the protection of animals used for scientific purposes.

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The research did not involve human participants.

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Loi, M., Salvatore, G., Sottili, M. et al. Tumor-associated macrophages (TAMs) modulate response to HER2-targeted agents in a humanized mouse model of breast cancer. Clin Transl Oncol 24, 1395–1402 (2022). https://doi.org/10.1007/s12094-022-02785-z

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