Efficacy of CTLA-4 checkpoint therapy is dependent on IL-21 signaling to mediate cytotoxic reprogramming of PD-1+CD8+ T cells

IF 27.7 1区 医学 Q1 IMMUNOLOGY Nature Immunology Pub Date : 2024-12-19 DOI:10.1038/s41590-024-02027-0
Zhen Zhang, Marlene Langenbach, Sagar Sagar, Viktor Fetsch, Jonas Stritzker, Elizabeth Severa, Ke Meng, Frances Winkler, Nisha Rana, Katharina Zoldan, Ira Godbole, Sabrina Solis, Jeffrey S. Weber, David Rafei-Shamsabadi, Saskia Lehr, Rebecca Diehl, Ana Cecilia Venhoff, Reinhard E. Voll, Nico Buettner, Christoph Neumann-Haefelin, Tobias Boettler, Maike Hofmann, Melanie Boerries, Frank Meiss, Robert Zeiser, Robert Thimme, Ramin S. Herati, Bertram Bengsch
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Abstract

The mechanisms underlying the efficacy of anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) therapy are incompletely understood. Here, by immune profiling responding PD-1+CD8+ T (TResp) cell populations from patients with advanced melanoma, we identified differential programming of TResp cells in response to combination therapy, from an exhausted toward a more cytotoxic effector program. This effect does not occur with anti-PD-1 monotherapy. Single-cell transcriptome and T cell receptor repertoire analysis was used to identify altered effector programming of expanding PD-1+CD8+ T cell clones with distinct regulon usage, STAT1 and STAT3 utilization and antitumor specificity connected to interleukin (IL)-21 signaling in combination and anti-CTLA-4 monotherapy. Therapeutic efficacy of CTLA-4 blockade was lost in B16F10 melanoma models with either Il21r− deficiency or anti-IL-21 receptor blockade. Together, these results show how IL-21 signaling to TResp is critical for anti-CTLA-4-based checkpoint therapies and highlight major signaling differences to anti-PD-1 monotherapy. Here the authors dissect the contribution of IL-21 signaling to immune checkpoint-responding CD8+ T cells from mouse models and patients being treated for advanced melanoma.

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来源期刊
Nature Immunology
Nature Immunology 医学-免疫学
CiteScore
40.00
自引率
2.30%
发文量
248
审稿时长
4-8 weeks
期刊介绍: Nature Immunology is a monthly journal that publishes the highest quality research in all areas of immunology. The editorial decisions are made by a team of full-time professional editors. The journal prioritizes work that provides translational and/or fundamental insight into the workings of the immune system. It covers a wide range of topics including innate immunity and inflammation, development, immune receptors, signaling and apoptosis, antigen presentation, gene regulation and recombination, cellular and systemic immunity, vaccines, immune tolerance, autoimmunity, tumor immunology, and microbial immunopathology. In addition to publishing significant original research, Nature Immunology also includes comments, News and Views, research highlights, matters arising from readers, and reviews of the literature. The journal serves as a major conduit of top-quality information for the immunology community.
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