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

Gamma delta T cells (gamma delta Tc) have tremendous anti-tumoral activity, thus gamma delta Tc 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 gamma delta Tc immunotherapy, yet some escaped. The BCSC secretome rendered gamma delta Tc 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 gamma delta Tc. Increased MICA shedding was prevented by the ADAM in-hibitor GW280264X, rendering BCSC as sensitive to gamma delta Tc cytotoxicity as NSC. Our data show promising potential for gamma delta Tc 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.