Inflammasomes within hyperactive dendritic cells stimulate T cell mediated anti-tumor immunity

Central to anti-tumor immunity are dendritic cells (DCs), which can stimulate long-lived protective T cell responses. Recent studies have demonstrated that DCs can achieve a state of hyperactivation, which is associated with inflammasome activities within living cells. Herein, we report that hyperactive DCs have an enhanced ability to migrate to draining lymph nodes and stimulate potent cytotoxic T lymphocyte (CTL) responses. This enhanced migratory activity is dependent on the chemokine receptor CCR7 and is associated with a unique transcriptional program that is not observed in conventionally activated or pyroptotic DCs. We discovered that hyperactivating stimuli are uniquely capable of inducing durable CTL-mediated anti-tumor immunity against tumors that are sensitive or resistant to PD-1 inhibition. These protective responses are intrinsic to the cDC1 subset of DCs, depend on the inflammasome-dependent cytokine IL-1ß and enable tumor lysates to serve as immunogens. Therefore, hyperactive DCs may diversify current approaches to cancer immunotherapy. Overall design: RNA-seq readout of 3 biological replicates of induced FLT3 cDC1 or FLT3 cDC2 mouse cells treated with 'Nothing', 'LPS', 'LPS&PGPC', 'PGPC', 'LPS&Alum', and 'Alum'