1118 Immunologically relevant effects of PT-112 on cancer cell mitochondria

Background PT-112 is a novel platinum-pyrophosphate conju-gate 1 under clinical development for cancer therapy. 2-5 Besides mediating cytostatic and cytotoxic effects in numerous human and mouse cancer cells, PT-112 elicits various danger signals that are linked to immunogenic cell death (ICD), such as cal-reticulin exposure, as well as ATP and HMGB1 secretion. 3,6,7 Accordingly, mouse cancer cells succumbing to PT-112 in vitro efficiently protect immunocompetent, tumor-naïve mice from challenge with living cancer cells of the same type. 6,7 More-over, PT-112 synergizes with PD-1 or PD-L1 blockade to con-trol mouse tumors developing in immunologically competent hosts. 6,7 In some tumor models, robust type I interferon (IFN) signaling is required for ICD 8-10 However, the role of type I IFN signaling in the immunogenicity of PT-112 remains unclear. Methods We used wild-type, mitochondrial DNA (mtDNA) depleted (rho 0 ), as well as Casp2 -/- and Casp3 -/- mouse TS/A cells. 11 ELISA, flow cytometry and immunofluorescence micro-scopy were employed to monitor type I IFN levels, reactive oxygen species (ROS) generation, mitochondrial polarization, cell death, and cytosolic dsDNA accumulation driven by PT-112 and underlying regulatory mechanisms. Results TS/A cells, PT-112 induced mitochondrial dysfunction, as demonstrated by ROS generation and mitochondrial hyperpolarization, as well as cytosolic accumulation of dsDNA that was abrogated in rho 0 TS/A cells. Type I IFN secretion by wild-type TS/A responding to PT-112

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