Cell-specific nanoengineering strategy disrupts tolerogenic signaling from myeloid-derived suppressor cells to invigorate antitumor immunity in pancreatic cancer

Deshpande, N. U.; Bianchi, A.; Amirian, H.; De Castro Silva, I.; Rafie, C. I.; Surnar, B.; Rajkumar, K.; Ogobuiro, I.; Patel, M.; Mehra, S.; Nagathihalli, N.; Merchant, N. B.; Dhar, S.; Datta, J.

doi:10.1101/2024.05.25.594901

bioRxiv · 10.1101/2024.05.25.594901

Cell-specific nanoengineering strategy disrupts tolerogenic signaling from myeloid-derived suppressor cells to invigorate antitumor immunity in pancreatic cancer

Deshpande, N. U.·Bianchi, A.·Amirian, H.·De Castro Silva, I.·Rafie, C. I.·Surnar, B.·Rajkumar, K.·Ogobuiro, I.·Patel, M.·Mehra, S.·Nagathihalli, N.·Merchant, N. B.·Dhar, S.·Datta, J.

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by intratumoral abundance of neutrophilic/polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) which inhibit T-cell function through JAK2/STAT3-regulated arginase activity. To overcome limitations of systemic inhibition of PMN-MDSCs in cancer-bearing patients--i.e., neutropenia and compensatory myelopoietic adaptations--we develop a nanoengineering strategy to target cell-specific signaling exclusively in PMN-MDSCs without provoking neutropenia. We conjugate a chemically modified small-molecule inhibitor of MDSC-surface receptor CXCR2 (AZD5069) with polyethylene glycol (PEG) and chemically graft AZD5069-PEG constructs onto amphiphilic polysaccharide derivatives to engineer CXCR2-homing nanoparticles (CXCR2-NP). Cy5.5 dye-loaded CXCR2-NP showed near-exclusive uptake in PMN-MDSCs compared with PDAC tumor-cells, cancer-associated fibroblasts, and macrophages. Encapsulation of JAK2/STAT3i Ruxolitinib (CXCR2-NPRuxo) resulted in more durable attenuation in STAT3-regulated arginase activity from PMN-MDSCs and induction of cytolytic T-cell activity vs. free Ruxolitinib in-vitro and in-vivo. Cell-specific delivery of payloads via CXCR2-homing immunonanoparticles represents a novel strategy to disrupt MDSC-mediated immunosuppression and invigorate antitumor immunity in PDAC.

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Deshpande, N. U., Bianchi, A., Amirian, H., De Castro Silva, I., Rafie, C. I., Surnar, B., Rajkumar, K., Ogobuiro, I., Patel, M., Mehra, S., Nagathihalli, N., Merchant, N. B., Dhar, S., Datta, J.. 2024-05-30. Cell-specific nanoengineering strategy disrupts tolerogenic signaling from myeloid-derived suppressor cells to invigorate antitumor immunity in pancreatic cancer. https://doi.org/10.1101/2024.05.25.594901

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