Abstract A004: Stromal-targeting payloads are not functionally equivalent in pancreatic cancer: Decorin-armed VSV couples matrix remodeling with systemic immune reprogramming
Sina Aslanabadi, Garima Sinha, Olivia Hart, Amirsalar Mansouri, Dorota Wyczechowska, Dicle Yalcin, Sudhakar Ammanamanchi, Mitesh Borad, John West, Jiri Adamec, Bolni Marius. Nagalo, Omeed MoavenAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) has a dense desmoplastic stroma that restricts drug and immune-cell delivery, sustains immunosuppression, and limits oncolytic virus efficacy. Stromal-depletion strategies have failed clinically; PEGylated hyaluronidase (PEGPH20) improved response rates without improving survival in phase III. We hypothesized that stromal restoration through decorin would couple extracellular matrix (ECM) remodeling with antitumor immunity more effectively than degradative approaches, and engineered replication-competent M51R-VSV expressing decorin (VSV-DCN), relaxin (VSV-RLX), or hyaluronidase (VSV-PH20).
Methods:
Six human PDAC lines and nonmalignant H6C7 cells were evaluated for viral replication, viability, apoptosis, decorin secretion, spheroid disruption, invasion, and clonogenicity. Syngeneic KPC tumors received intratumoral PBS, VSV-GFP, VSV-DCN, VSV-RLX, or VSV-PH20 (1×10^9 TCID50; days 1, 4, and 7; n=6–10/group). Separate cohorts underwent immunohistochemistry, LC-MS proteomics, bulk RNA sequencing, or orthotopic survival analysis. Immune populations were quantified by flow cytometry as percentages of live cells.
Results:
All VSVs induced dose-dependent oncolysis and apoptosis and disrupted PDAC spheroids while largely sparing H6C7 cells; only VSV-PH20 reduced H6C7 viability at MOI 10. VSV-DCN secreted decorin dose- and time-dependently. VSV-PH20 increased invasion in three of four PDAC lines, with significant increases in a subset, whereas VSV-DCN did not. VSV-DCN reduced collagen deposition and increased intratumoral decorin and apoptosis. At 72 hours, VSV-G was tumor-restricted, with no detection in liver, spleen, lung, or brain. Proteomics demonstrated innate and adaptive immune activation, including macrophage, leukocyte-extravasation, antigen-presentation, CSF1, and T-cell receptor pathways, whereas comparator payloads showed minimal immune-pathway enrichment. Independent RNA sequencing identified remodeling of ECM-receptor, leukocyte-migration, HIF-1, metabolic, and Th1/Th2 programs. Flow cytometry showed 12.6-fold more intratumoral CD8+ T cells, 15.7-fold more granzyme B+ effectors, 3.4-fold more CD3+ T cells, and 73% fewer monocytic MDSCs (p=0.006). Contralateral tumors showed concordant T-cell expansion (15.9-fold CD8+; 3.9-fold CD3+, p=0.06). In orthotopic KPC models, VSV-DCN prolonged survival versus control (p<0.01) and was the only stromal-targeting payload to outperform VSV-GFP (p<0.05).
Conclusions:
Stromal-targeting payloads were not biologically equivalent. Unlike degradative ECM approaches, decorin remodeled the desmoplastic matrix and reprogrammed local and systemic antitumor immunity, converting immune-excluded PDAC into a CD8-rich, MDSC-depleted microenvironment. These findings establish decorin-armed VSV as a stromal-immune priming platform for rational combination with chemotherapy, immune checkpoint blockade, and KRAS-targeted therapies.
Citation Format:
Sina Aslanabadi, Garima Sinha, Olivia Hart, Amirsalar Mansouri, Dorota Wyczechowska, Dicle Yalcin, Sudhakar Ammanamanchi, Mitesh Borad, John West, Jiri Adamec, Bolni Marius. Nagalo, Omeed Moaven. Stromal-targeting payloads are not functionally equivalent in pancreatic cancer: Decorin-armed VSV couples matrix remodeling with systemic immune reprogramming [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A004.