Tissue factor promotes TREX1 protein stability to evade cGAS-STING innate immune response in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains the most challenging human malignancy that urgently needs effective therapy. Tissue factor (TF) is expressed in ~80% of PDAC and represents a potential therapeutic target. While a novel TF-ADC (MRG004A) demonstrated efficacy for PDAC and TNBC in a Phase I/II trial [Ref. 18], the functional role of TF in PDAC remains incompletely understood. We investigated the relationship between TF and the innate STING pathway. We found that patients with TF-overexpression had poor survival, very low levels of P-STING/P-TBK1, reduced amounts of ISGs and chemokines as well as low numbers of cytotoxic immunocytes in their tumor. In experimental models of mouse and human PDAC, tumor cell-intrinsic TF expression played a major role in silencing the cytosolic micronuclei sensing and cGAS-STING activation. This process involved a TREX1 exonuclease-dependent clearance of micronucleus-DNA accumulated in tumor cells. Treatment of tumors with TF-KO/shRNA or anti-TF antibody HuSC1-39 (parent antibody of MRG004A) triggered a rapid and proteasome-dependent degradation of TREX1 thereby restoring the STING/TBK1 cascade phosphorylation. TF-inhibition therapy promoted a robust STING/IRF3-dependent IFN/CCL5/CXCL9-11 production, immune effector cell infiltration and antitumor efficacy. Moreover, in the PBMC and cancer cell co-culture, TF-inhibition synergized with a STING agonist compound. A covalently conjugated TF antibody-STING agonist ADC strongly increased the efficacy of tumor-targeted STING agonism on chemokine secretion and tumor inhibition in vitro and in vivo. Thus, TF-inhibition reshapes an "immune hot" tumor environment. TF-targeted therapy warrants clinical investigation as a single agent or in combination with immunotherapy for treating TF-positive PDAC and TNBC.

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