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Breast Cancer Stem Cell-Derived Tumors Escape from γδ T-cell Immunosurveillance In Vivo by Modulating γδ T-cell Ligands

  • There are no targeted therapies for patients with triple-negative breast cancer (TNBC). TNBC is enriched in breast cancer stem cells (BCSC), which play a key role in metastasis, chemoresistance, relapse, and mortality. γδ T cells hold great potential in immunotherapy against cancer and might provide an approach to therapeutically target TNBC. γδ T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor-sensing mechanisms, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. Herein, we show that patient-derived triple-negative BCSCs are efficiently recognized and killed by ex vivo expanded γδ T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to γδ T-cell immunotherapy. We unraveled concerted differentiation and immune escape mechanisms: xenografted BCSCs lost stemness, expression of γδ T-cell ligands, adhesion molecules, and pAgs, thereby evading immune recognition by γδ T cells. Indeed, neither promigratory engineered γδ T cells, nor anti–PD-1 checkpoint blockade, significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the γδ T cells and could be pharmacologically reverted by zoledronate or IFNα treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.

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Document Type:Article
Author:Katrin RauteORCiD, Juliane StrietzORCiD, Maria Alejandra ParigianiORCiD, Geoffroy AndrieuxORCiD, Oliver S. ThomasORCiD, Klaus M. KistnerORCiD, Marina ZintchenkoORCiD, Peter AicheleORCiD, Maike HofmannORCiD, Houjiang ZhouORCiD, Wilfried WeberORCiD, Melanie BoerriesORCiD, Mahima SwamyORCiD, Jochen MaurerORCiD, Susana MinguetORCiD
Parent Title (English):Cancer Immunology Research
First Page:810
Last Page:829
Year of first Publication:2023
Release Date:2023/06/30
Impact:12.020 (2021)
Funding Information:German Research Foundation (DFG) through BIOSS - EXC294 and CIBSS - EXC 2189 SFB850 SFB1479 (project ID: 441891347 - P15) SFB1160 (project ID 256073931 - B01) FOR2799 (MI1942/3-1) SFB1453 (project ID 431984000 - S1 ) TRR167 (project ID 259373024 - Z01). German Federal Ministry of Education and Research by MIRACUM within the Medical Informatics Funding Scheme (FKZ 01ZZ1801B and EkoEstMed-FKZ 01ZZ2015 ) Dutch Cancer Society (KWF project ID: 13043). DFG through GSC-4 (Spemann Graduate School). Wellcome Trust (206246/Z/17/Z) Henry Dale Fellowship.
Scientific Units:Materials Synthetic Biology
DDC classes:600 Technik, Medizin, angewandte Wissenschaften / 610 Medizin, Gesundheit
Open Access:Open Access
Signature:INM 2023/078
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International