Local delivery of cell surface-targeted immunocytokines programs systemic anti-tumor immunity

• Published in: bioRxiv
• Main Authors: Santollani, Luciano, Zhang, Yiming J, Maiorino, Laura, Palmeri, Joseph R, Stinson, Jordan A, Duhamel, Lauren R, Qureshi, Kashif, Suggs, Jack R, Porth, Owen T, Pinney, 3rd, William, Msari, Riyam Al, Wittrup, K Dane, Irvine, Darrell J
• Format: Journal Article Paper
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 03.01.2024
• Subjects: Animal models; Antiviral agents; CD45 antigen; CD8 antigen; Cell surface; Cytokines; Immunity; Immunotherapy; Leukocytes; Lymph nodes; Lymphocytes T; Tumors
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2024.01.03.573641

Cytokine therapies are potent immunotherapy agents but exhibit severe dose-limiting toxicities. One strategy to overcome this involves engineering cytokines for intratumoral retention following local delivery. Here, we develop a localized cytokine therapy that elicits profound anti-tumor immunity by engineered targeting to the ubiquitous leukocyte receptor CD45. We designed CD45-targeted immunocytokines (αCD45-Cyt) that, upon injection, decorated the surface of leukocytes in the tumor and tumor-draining lymph node (TDLN) without systemic exposure. αCD45-Cyt therapy eradicated both directly treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models. Mechanistically, αCD45-Cyt triggered prolonged pSTAT signaling and reprogrammed tumor-specific CD8 T cells in the TDLN to exhibit an anti-viral transcriptional signature. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.