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

TY - JOUR

T1 - Breast Cancer Stem Cell-Derived Tumors Escape from γδ T-cell Immunosurveillance In Vivo by Modulating γδ T-cell Ligands

AU - Raute, Katrin

AU - Strietz, Juliane

AU - Parigiani, Maria Alejandra

AU - Andrieux, Geoffroy

AU - Thomas, Oliver S.

AU - Kistner, Klaus M.

AU - Zintchenko, Marina

AU - Aichele, Peter

AU - Hofmann, Maike

AU - Zhou, Houjiang

AU - Weber, Wilfried

AU - Boerries, Melanie

AU - Swamy, Mahima

AU - Maurer, Jochen

AU - Minguet, Susana

N1 - Funding Information: This study was supported by the German Research Foundation (DFG) through BIOSS- EXC294 and CIBSS - EXC 2189 to S. Minguet; SFB850 (C10 to S. Minguet, C9 and Z01 to M. Boerries), SFB1479 (project ID: 441891347-P15 to S. Minguet and S1 to M. Boerries), SFB1160 (project ID 256073931-B01 to S. Minguet and Z02 to M. Boerries), FOR2799 (MI1942/3-1 to S. Minguet) and SFB1453 (project ID 431984000-S1 to M. Boerries) and TRR167 (projectID 259373024-Z01 to M. Boerries). This project was partially supported by the German Federal Ministry of Education and Research by MIRACUM within the Medical Informatics Funding Scheme (FKZ01ZZ1801B to M. Boerries and Eko Est Med- FKZ01ZZ2015 to G. Andrieux) and by the Dutch Cancer Society (KWF project ID: 13043). K. Raute was supported by DFG through GSC-4 (Spemann Graduate School). M. Swamy was funded by a Wellcome Trust (206246/Z/17/Z) Henry Dale Fellowship. Copyright: ©2023 The Authors; Published by the American Association for Cancer Research.

PY - 2023/6/2

Y1 - 2023/6/2

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85160970300

U2 - 10.1158/2326-6066.CIR-22-0296

DO - 10.1158/2326-6066.CIR-22-0296

M3 - Article

C2 - 37139603

SN - 2326-6066

VL - 11

SP - 810

EP - 829

JO - Cancer Immunology Research

JF - Cancer Immunology Research

IS - 6

ER -