Triple negative breast cancer (TNBC) lacks targeted therapy options. TNBC is enriched in breast cancer stem cells (BCSCs), which play a key role in metastasis, chemoresistance, relapse and mortality. γδ T cells hold great potential in immunotherapy against cancer, and might be an alternative to target TNBC. γδ T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor sensing, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. 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. Mechanistically, we unraveled concerted differentiation and immune escape: xenografted BCSCs lost stemness, expression of γδ T cell ligands, adhesion molecules and pAgs, thereby evading immune recognition by γδ T cells. Indeed, neither pro-migratory 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 IFN-α treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.
Katrin Raute, Juliane Strietz, Geoffroy Andrieux, Oliver S. Thomas, Klaus M. Kistner, Marina Zintchenko, Peter Aichele, Houjiang Zhou, Wilfried Weber, Melanie Boerries, Mahima Swamy, Jochen Maurer, Susana Minguet