ADAM protease inhibition overcomes resistance of breast cancer stem-like cells to γδ T cell immunotherapy

Gamma delta T cells (γδTc) have tremendous anti-tumoral activity, thus γδTc immunotherapy is currently under development for various malignancies. We targeted breast cancer stem-like cells (BCSC), a rare cell population responsible for patient mortality. BCSC were mostly susceptible to γδTc immunotherapy, yet some escaped. The BCSC secretome rendered γδTc hypo-responsive, and resistant BCSC expressed more PD-L1 and anti-apoptotic protein MCL-1 than non-stem-like cells (NSC). BCSC resistance was partially overcome by dMCL1-2, an MCL-1 degrader, or more fully by blocking PD-1 on γδTc. Increased MICA shedding was prevented by the ADAM inhibitor GW280264X, rendering BCSC as sensitive to γδTc cytotoxicity as NSC. Our data show promising potential for γδTc immunotherapy against BCSC while unraveling immune evasion mechanisms exploited by BCSC, which likely also enable their resistance to cytotoxic T and NK cells. Overcoming this resistance, as we have done here, will improve cancer immunotherapy, leading to better cancer patient outcomes. •Breast cancer stem-like cells (BCSC) use multiple mechanisms to evade γδ T cells.•Blocking PD-1 partially reverses BCSC resistance to γδ T cell cytotoxicity.•Targeting the anti-apoptotic protein MCL-1 increases BCSC sensitivity.•BCSC express lower MICA on the cell surface and shed more MICA than non-BCSC .•ADAM inhibition prevents MICA shedding, overcoming BCSC resistance to γδTc.