 PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cellsLaura Codarri Deak,
Valeria Nicolini,
Masao Hashimoto,
Maria Karagianni,
Petra C. Schwalie,
Laura Lauener,
Eleni Maria Varypataki,
Marine Richard,
Esther Bommer,
Johannes Sam,
Stefanie Joller,
Mario Perro,
Floriana Cremasco,
Leo Kunz,
Emilio Yanguez,
Tamara Hüsser,
Ramona Schlenker,
Marisa Mariani,
Vinko Tosevski,
Sylvia Herter,
Marina Bacac,
Inja Waldhauer,
Sara Colombetti,
Xavier Gueripel,
Stephan Wullschleger,
Melanie Tichet,
Douglas Hanahan,
Haydn T. Kissick,
Stephane Leclair,
Anne Freimoser-Grundschober,
Stefan Seeber,
Volker Teichgräber,
Rafi Ahmed,
Christian Klein () and
Pablo Umaña ()
Nature, 2022, vol. 610, issue 7930, 161-172 Abstract: Abstract Expansion and differentiation of antigen-experienced PD-1+TCF-1+ stem-like CD8+ T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade1–4. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of ‘better effector’ CD8+ T cells similar to those generated in an acute infection5. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists are currently being developed6–10. Here we show that IL-2Rβγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell recovers the ability to differentiate stem-like CD8+ T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections. Date: 2022 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:610:y:2022:i:7930:d:10.1038_s41586-022-05192-0 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-022-05192-0 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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