Preliminary testing of PEGPH20/shIDO-ST in autochthonous KPC-Brca1 mouse model. PMN and DAPI immunofluorescence staining of an autochthonous tumor section from a KPC-Brca1 mouse treated with PEGPH20/shIDO-ST. Tumor was excised, flash frozen, sectioned, and stained 5 days following treatment. Central DAPI negative region of tumor with neutrophils (red) is depicted at 10X magnification with DAPI+ tumor cells (blue) at upper right (T).
ARTICLE ABSTRACTBacterial-based therapies are emerging as effective cancer treatments and hold promise for refractory neoplasms, such as pancreatic ductal adenocarcinoma (PDAC), which has not shown significant improvement in therapy for more than 25 years. Using a novel combination of shIDO-ST, a Salmonella-based therapy targeting the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO), with an enzyme, PEGPH20, which depletes extracellular matrix hyaluronan, we observed extended survival with frequent total regression of autochthonous and orthotopic PDAC tumors. This observation was associated with migration and accumulation of activated polymorphonuclear neutrophils (PMN) from spleens into tumors, which was not seen using a scrambled control (shScr-ST). Purified splenic PMNs from PEGPH20/shIDO-ST-treated mice exhibited significant IDO knockdown and were able to kill tumor targets ex vivo through mechanisms involving FasL and serine proteases. In addition, CD8+ T cells were observed to contribute to late control of pancreatic tumors. Collectively, our data demonstrate that entry of shIDO-ST and PMNs into otherwise impermeable desmoplastic tumors is facilitated by PEGPH20-mediated HA removal, further highlighting an important component of effective treatment for PDAC. Cancer Immunol Res; 3(9); 1096–107. ©2015 AACR.