Rewiring STAT signaling from the cell surface with Trikine immunotherapeutics
Grayson E. Rodriguez, Yang Zhao, Yoko Nishiga, Frank Peprah, Jiao Shen, Gita C. Abhiraman, Masato Ogishi, Chenyu Zhang, Justin Saco, Deepa Waghray, Mamatha Serasanambati, Leonel Torres, Brandon W. Simone, Leon Su, Steven C. Wilson, Aerin Yang, Qinli Sun, Lora Picton, Robert A. Saxton, Vidit Bhandarkar, Madeline J. Lee, Elizabeth Andrews, Hua Jiang, Matthias Obenaus, Michelle Yen, Tavus Atajanova, Catherine A. Blish, Stefani Spranger, E. John Wherry, Amanda Kirane, Antoni Ribas, David H. Raulet, Anusha Kalbasi, Stephanie K. Dougan, Michael Dougan, Julien Sage, K. Christopher Garcia
Abstract
Cytokines dimerize two receptor chains to activate Janus kinases and signal transducer and activator of transcription (STAT) transcription factors that regulate immune cells, but they have therapeutic liabilities. We engineered “Trikines” to compel cis formation of three-chain cytokine receptor complexes at the cell surface that induce bespoke STAT transcriptional signaling programs. Trikines coactivated phosphorylation of STAT5 (pSTAT5) and pSTAT3 signatures distinct from natural cytokines by assembling trimeric combinations of interleukin-2 (IL-2), IL-10, and IL-21 receptors. In preclinical models, an IL-2–based Trikine restrained terminal differentiation of T cells, promoted stemness, and enhanced durability of tumor control without observable toxicity. An IL-10–based Trikine induced immune infiltration into poorly immunogenic tumors, showing efficacy in preclinical models of small cell lung cancer and pancreatic cancer. Trikines obviate the need for cell engineering to customize STAT signatures and may hold potential for immunotherapy.