Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity

Significance Radiotherapy is one of the most common forms of cancer treatment used today. Its impact in directly killing cancer cells, and on antitumour immunity, is well recognized, but its effect on immune cell–cancer cell interactions is not fully understood. Here, we show that irradiation of cancer cells surprisingly leads to resistance against immune cell cytotoxicity. This was mediated by a reduced susceptibility to the pore-forming protein perforin. Resistance manifested as a reduction in both necrotic death following osmotic lysis and apoptotic death following granzyme B uptake. Overall, these data establish a form of treatment-induced resistance to lymphocyte cytotoxicity. These findings have significant implications for the optimal design of radiotherapy–immunotherapy protocols.