Xenogeneic equine stem cells activate anti-tumor adaptive immunity in a 4T1-based intraductal mouse model for triple-negative breast cancer: proof-of-principle

Jonas Steenbrugge; Glenn Pauwelyn; Kristel Demeyere; Nausikaa Devriendt; Hilde de Rooster; Niek N Sanders; Jan H Spaas; Evelyne Meyer

doi:10.3389/fimmu.2023.1252374

Xenogeneic equine stem cells activate anti-tumor adaptive immunity in a 4T1-based intraductal mouse model for triple-negative breast cancer: proof-of-principle

Front Immunol. 2023 Oct 20:14:1252374. doi: 10.3389/fimmu.2023.1252374. eCollection 2023.

Authors

Jonas Steenbrugge^{1

2}, Glenn Pauwelyn³, Kristel Demeyere¹, Nausikaa Devriendt⁴, Hilde de Rooster^{2

4}, Niek N Sanders^{2

5}, Jan H Spaas^{6

7}, Evelyne Meyer^{1

2}

Affiliations

¹ Laboratory of Biochemistry, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
² Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
³ Boehringer Ingelheim Veterinary Medicine Belgium, Evergem, Belgium.
⁴ Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
⁵ Laboratory of Gene Therapy, Department of Veterinary and Biosciences, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
⁶ Department of Morphology, Imaging, Orthopedics, Rehabilitation and Nutrition, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
⁷ Boehringer-Ingelheim Animal Health USA, Athens, GA, United States.

Abstract

Triple-negative breast cancer (TNBC) remains difficult to treat, especially due to ineffective immune responses. Current treatments mainly aim at a cytotoxic effect, whereas (stem) cell therapies are being investigated for their immune stimulatory capacities to initiate the anti-tumor immunity. Here, a thoroughly characterized, homogenous and non-tumorigenic mixture of equine mesenchymal stem cells (eMSCs) harvested from horse peripheral blood as innovative xenogeneic immunomodulators were tested in a 4T1-based intraductal mouse model for TNBC. The eMSCs significantly reduced 4T1 progression upon systemic injection, with induction of inflammatory mediators and T-cell influx in primary tumors, already after a single dose. These xenogeneic anti-cancer effects were not restricted to MSCs as systemic treatment with alternative equine epithelial stem cells (eEpSCs) mimicked the reported disease reduction. Mechanistically, effective eMSC treatment did not rely on the spleen as systemic entrapment site, whereas CD4⁺ and CD8α⁺ T-cell infiltration and activation were critical. These results show that eMSCs and potentially also other equine stem cell types can be a valuable TNBC treatment strategy for further (pre)clinical evaluation.

Keywords: equine stem cells; immunotherapy; intraductal model; triple-negative breast cancer; xenogeneic.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity
Animals
Antineoplastic Agents* / therapeutic use
Horses
Humans
Mesenchymal Stem Cells*
Mice
Signal Transduction
Triple Negative Breast Neoplasms* / pathology

Substances

Antineoplastic Agents

Grants and funding

This work was in part supported by a junior postdoctoral fellowship from the Research Foundation Flanders (FWO, 12Y3122N) awarded to JS, a grant from the Fund Suzanne Duchesne (managed by the King Baudouin Foundation) awarded to JS and a grant from the Research Foundation Flanders (FWO, G.0621.10) awarded to NNS.