Induced loss of TREX1 in host cells inflames the tumor micromilieu and invigorates CTL-mediated cancer control
Activation of local innate immunity in tumor tissue, aiming at induction of adaptive responses, is a major concept in cancer immunotherapy. The cGAS/STING pathway triggers type I IFN and pro-inflammatory cytokine responses upon detection of cytosolic DNA and can robustly enhance anti-tumor immunity. The DNase 3' repair exonuclease 1 (TREX1) is a central component of cellular DNA disposal preventing accumulation of endogenous DNA in the cytosol, activation of cGAS and cell-intrinsic innate immune responses. While constitutive TREX1-deficiency causes severe mendelian autoimmunity, temporary pharmacological inhibition of the enzyme may represent an efficient means to activate anti-tumor immunity. Induced inactivation of the Trex1 gene in mice (TREX1 iKO) resulted in improved immune control of established syngeneic tumors that was type I IFN- and CD8+ T cell-dependent. This was associated with a dramatic increase of immune cell infiltration of tumor tissue while other (non-tumor) tissues were not or marginally affected. TREX1 iKO triggered an inflammatory switch of intra-tumoral monocyte, macrophage and dendritic cell populations, associated with enhanced antigen presentation capacity. Invigoration of CD8 T cell responses was reflected in robust increase in cells differentiating along the exhaustion trajectory but expressing significant signatures of effector function. Combination of TREX1 iKO with immune checkpoint inhibition synergistically promoted tumor control. In addition to improved anti-tumor immunity upon loss of TREX1 in host cells, we also show that cancer cell-specific TREX1 deficiency synergizes with irradiation and checkpoint inhibition to enable tumor rejection and formation of long-term memory. We conclude that pharmacological TREX1 inhibition is a promising therapeutic approach to boost anti-tumor immunity. Overall design: To illustrate how the Trex1 knockout-induced immune response regulates tumor growth, an inducible Trex1 knockout mouse model bearing syngeneic melanoma B16 tumors was used to generate the single cell RNAseq data of tumor-infiltrating-Immune cells.