Breast cancer stem cell-derived tumors escape from γδ T cell immunosurveillance in vivo by modulating γδ T cell ligands
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. {gamma}{delta} T cells hold great potential in immunotherapy against cancer, and might be an alternative to target TNBC. {gamma}{delta} 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 {gamma}{delta} T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to {gamma}{delta} T cell immunotherapy. Mechanistically, we unraveled concerted differentiation and immune escape: xenografted BCSCs lost stemness, expression of {gamma}{delta} T cell ligands, adhesion molecules and pAgs, thereby evading immune recognition by {gamma}{delta} T cells. Indeed, neither pro-migratory engineered {gamma}{delta} 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 {gamma}{delta} T cells, and could be pharmacologically reverted by Zoledronate or IFN- treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.