23266066cir140214-sup-141035_2_supp_3002942_npmkbz.pptx (78.62 kB)

Supplementary Fig. S15 from Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Coupled with Enzymatic Depletion of Tumor Hyaluronan Induces Complete Regression of Aggressive Pancreatic Tumors

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posted on 2023-04-03, 23:03 authored by Edwin R. Manuel, Jeremy Chen, Massimo D'Apuzzo, Melanie G. Lampa, Teodora I. Kaltcheva, Curtis B. Thompson, Thomas Ludwig, Vincent Chung, Don J. Diamond

Chromium release assay utilizing a range of PMN (effectors) against various tumor targets. Purified splenic PMN from treated mouse groups (n=3) were used in a 51Cr cytotoxicity assay. Tumor targets consisted of KPC (pancreatic cancer), 4T1 (breast cancer), and B16F10 (melanoma) which were co-incubated directly with effectors at indicated E:T ratios. Each E:T ratio with specific tumor targets were done in triplicate. Percent lysis within the PEGPH20/shIDO-ST group was compared to the PEGPH20/shScr-ST treated group at each E:T ratio using Student's t test. Data shown is representative of multiple experiments.

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ARTICLE ABSTRACT

Bacterial-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.