Sensitizing solid tumors to remote killing by T-cells 3188

Description Although contact-dependent, perforin-mediated cytotoxicity is crucial for T cell-mediated immunity, it is an inefficient method of eliminating unwanted cells. This is because the directional release of cytotoxic granules across the immunological synapse allows only one target cell to be killed at a time. This serial killing approach is likely insufficient at controlling rapid infections or an influx of malignant cells. One explanation for the poor effectiveness of CAR-T cells at treating solid tumors may be that the low efficiency contact-dependent killing of target cells require high effector:target (E:T) ratio may not be attainable clinically. Thus, developing strategies that enable T cells to kill tumor targets at a higher efficiency (i.e., lower E:T ratio) is warranted. Using a murine CAR-T system, we observed a direct role for T cell-derived cytokines in killing tumor target cells. As these effector molecules are diffusible, we found that this killing did not require effector-to-target contact but rather killed in a “remote” manner. Furthermore, we found that remote killing can be substantially improved if we inhibit TNF signaling molecules in the target cells that are often disabled by pathogens. Thus, tumor targets that are deficient in TAK1, HOIP or TBK1/IKKε can be killed by CAR-T cells at low E:T ratios. This work suggests that concurrently inhibiting certain TNF signaling molecules may be a strategy to augment CAR-T cell therapy for improved clinical outcome.