Rewiring STAT signaling from the cell surface with Trikine immunotherapeutics.
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| Title: | Rewiring STAT signaling from the cell surface with Trikine immunotherapeutics. |
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| Authors: | Rodriguez, Grayson E. (AUTHOR), Zhao, Yang (AUTHOR), Nishiga, Yoko (AUTHOR), Peprah, Frank (AUTHOR), Shen, Jiao (AUTHOR), Abhiraman, Gita C. (AUTHOR), Ogishi, Masato (AUTHOR), Zhang, Chenyu (AUTHOR), Saco, Justin (AUTHOR), Waghray, Deepa (AUTHOR), Serasanambati, Mamatha (AUTHOR), Torres, Leonel (AUTHOR), Simone, Brandon W. (AUTHOR), Su, Leon (AUTHOR), Wilson, Steven C. (AUTHOR), Yang, Aerin (AUTHOR), Sun, Qinli (AUTHOR), Picton, Lora (AUTHOR), Saxton, Robert A. (AUTHOR), Bhandarkar, Vidit (AUTHOR) |
| Source: | Science. 5/14/2026, Vol. 392 Issue 6799, p1-21. 21p. |
| Subjects: | Interleukin-2, Interleukin-10, Immunotherapy, T cells, Cancer treatment, JAK-STAT pathway, Cytokines, Cellular signal transduction |
| 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. Editor's summary: Cytokines are molecular messengers that modulate immune responses. Rodriguez et al. designed hybrid cytokines called Trikines that mediate intracellular signaling from the cell surface by assembling three-chain cytokine receptor complexes. By recruiting a third receptor chain into an endogenous cytokine receptor dimer, Trikines promoted STAT signaling and gene expression programs distinct from those generated by natural cytokines without the need for cellular engineering. The authors designed interleukin-2– and interleukin-10–based Trikines that tuned STAT3 and STAT5 signaling, reshaped immune cell states, and improved antitumor responses in experimental tumor models. Trikines may provide an engineering path to developing immunotherapies and unraveling new cytokine functions. —Priscilla N. Kelly INTRODUCTION: Cytokines are secreted proteins that modulate the immune system through dimerization of cell surface receptors. This dimerization activates Janus kinases, which induce gene expression through phosphorylation of signal transducer and activator of transcription (pSTAT) proteins. The functional effects of cytokines are largely determined by which STATs they activate, which, in turn, determines the gene expression programs. For example, interleukin-2 (IL-2) is a prototypical "pSTAT5" cytokine, which is important for T cell proliferation, whereas IL-10 and IL-21 are "pSTAT3" cytokines that help maintain cells in a stem-like state. The pSTAT programs associated with each natural cytokine are optimized for specific immune functions but not for therapeutic efficacy and tolerability. Cytokine receptor signaling machinery is modular, offering the possibility of a combinatorial "mix-and-match" engineering approach of receptors to elicit custom, tunable "non-natural" STAT signatures. Although such non-natural signatures may not have naturally evolved to benefit immune homeostasis, they may have new therapeutic utilities in immunotherapy. We sought to explore the preclinical therapeutic potential of non-natural cytokine receptor pairings to rewire and rebalance pSTAT profiles, using a new cytokine engineering approach. RATIONALE: We hypothesized that the recruitment of a third cytokine receptor to a natural cytokine signaling ternary complex would add additional pSTAT signaling that could be therapeutically beneficial. Specifically, we aimed to combine the signals of pSTAT5, which promotes T cell survival, and pSTAT3, which promotes T cell stemness and restrains T cell exhaustion. To test this, we developed "Trikines"—soluble ligands that induce three-chain cytokine receptor complexes on natural cells. RESULTS: We engineered an IL-2/21-Trikine, which recruits IL-21R to the IL-2/IL-2Rβ/γ chain (γc) ternary complex to induce pSTAT5/pSTAT3 signaling. Our human-reactive IL-2/21-Trikine enhanced T cell persistence and cytotoxicity in in vitro repeated antigen challenge assays. It also enhanced the proliferation and restrained the differentiation of tumor-infiltrating lymphocytes (TILs) isolated from melanoma patient samples, showing promise for its application in ex vivo TIL expansion. The mouse-reactive IL-2/21-Trikine demonstrated notable tolerability compared with IL-2 while also improving antitumor effects and maintaining T cell stemness in vivo. We explored whether pSTAT3/pSTAT5 combinations could provide enhanced therapeutic efficacy in experimental tumor models. We achieved this reciprocal pSTAT signaling profile with the IL-10/2-Trikine, which recruits IL-2Rβ to a ternary complex made up of a monomeric IL-10, IL-10Rα, and IL-10Rβ. Indeed, the IL-10/2-Trikine demonstrated antitumor effects: (i) as monotherapy in B16F10 melanoma and pancreatic ductal adenocarcinoma mouse models and (ii) in combination with anti–PD-1 immunotherapy, using human melanoma patient organoid cultures, the B16F10 melanoma mouse model, and KP1 small cell lung cancer mouse model. CONCLUSION: Trikines introduce a generalizable construction to design ligands with non-natural, tunable, combined pSTAT signals. Our data demonstrate that distinct pSTAT signals can be induced by soluble ligands in cell culture or administered in vivo, obviating the need for cell engineering to customize STAT signatures using preclinical immunotherapy models. Trikines are soluble ligands that tune pSTAT ratios and induce differential effects on T cells.: The Trikines that we investigated rewire pSTAT signaling of IL-2, IL-21, and IL-10, affecting T cell differentiation and stemness properties and antitumor durability. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| 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. Editor's summary: Cytokines are molecular messengers that modulate immune responses. Rodriguez et al. designed hybrid cytokines called Trikines that mediate intracellular signaling from the cell surface by assembling three-chain cytokine receptor complexes. By recruiting a third receptor chain into an endogenous cytokine receptor dimer, Trikines promoted STAT signaling and gene expression programs distinct from those generated by natural cytokines without the need for cellular engineering. The authors designed interleukin-2– and interleukin-10–based Trikines that tuned STAT3 and STAT5 signaling, reshaped immune cell states, and improved antitumor responses in experimental tumor models. Trikines may provide an engineering path to developing immunotherapies and unraveling new cytokine functions. —Priscilla N. Kelly INTRODUCTION: Cytokines are secreted proteins that modulate the immune system through dimerization of cell surface receptors. This dimerization activates Janus kinases, which induce gene expression through phosphorylation of signal transducer and activator of transcription (pSTAT) proteins. The functional effects of cytokines are largely determined by which STATs they activate, which, in turn, determines the gene expression programs. For example, interleukin-2 (IL-2) is a prototypical "pSTAT5" cytokine, which is important for T cell proliferation, whereas IL-10 and IL-21 are "pSTAT3" cytokines that help maintain cells in a stem-like state. The pSTAT programs associated with each natural cytokine are optimized for specific immune functions but not for therapeutic efficacy and tolerability. Cytokine receptor signaling machinery is modular, offering the possibility of a combinatorial "mix-and-match" engineering approach of receptors to elicit custom, tunable "non-natural" STAT signatures. Although such non-natural signatures may not have naturally evolved to benefit immune homeostasis, they may have new therapeutic utilities in immunotherapy. We sought to explore the preclinical therapeutic potential of non-natural cytokine receptor pairings to rewire and rebalance pSTAT profiles, using a new cytokine engineering approach. RATIONALE: We hypothesized that the recruitment of a third cytokine receptor to a natural cytokine signaling ternary complex would add additional pSTAT signaling that could be therapeutically beneficial. Specifically, we aimed to combine the signals of pSTAT5, which promotes T cell survival, and pSTAT3, which promotes T cell stemness and restrains T cell exhaustion. To test this, we developed "Trikines"—soluble ligands that induce three-chain cytokine receptor complexes on natural cells. RESULTS: We engineered an IL-2/21-Trikine, which recruits IL-21R to the IL-2/IL-2Rβ/γ chain (γc) ternary complex to induce pSTAT5/pSTAT3 signaling. Our human-reactive IL-2/21-Trikine enhanced T cell persistence and cytotoxicity in in vitro repeated antigen challenge assays. It also enhanced the proliferation and restrained the differentiation of tumor-infiltrating lymphocytes (TILs) isolated from melanoma patient samples, showing promise for its application in ex vivo TIL expansion. The mouse-reactive IL-2/21-Trikine demonstrated notable tolerability compared with IL-2 while also improving antitumor effects and maintaining T cell stemness in vivo. We explored whether pSTAT3/pSTAT5 combinations could provide enhanced therapeutic efficacy in experimental tumor models. We achieved this reciprocal pSTAT signaling profile with the IL-10/2-Trikine, which recruits IL-2Rβ to a ternary complex made up of a monomeric IL-10, IL-10Rα, and IL-10Rβ. Indeed, the IL-10/2-Trikine demonstrated antitumor effects: (i) as monotherapy in B16F10 melanoma and pancreatic ductal adenocarcinoma mouse models and (ii) in combination with anti–PD-1 immunotherapy, using human melanoma patient organoid cultures, the B16F10 melanoma mouse model, and KP1 small cell lung cancer mouse model. CONCLUSION: Trikines introduce a generalizable construction to design ligands with non-natural, tunable, combined pSTAT signals. Our data demonstrate that distinct pSTAT signals can be induced by soluble ligands in cell culture or administered in vivo, obviating the need for cell engineering to customize STAT signatures using preclinical immunotherapy models. Trikines are soluble ligands that tune pSTAT ratios and induce differential effects on T cells.: The Trikines that we investigated rewire pSTAT signaling of IL-2, IL-21, and IL-10, affecting T cell differentiation and stemness properties and antitumor durability. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adx9954 |
