Wang, Kevin and Coutifaris, Paulina and Brocks, David and Wang, Guanning and Azar, Tarek and Solis, Sabrina and Nandi, Ajeya and Anderson, Shaneaka and Han, Nicholas and Manne, Sasikanth and Kiner, Evgeny and Sachar, Chirag and Lucas, Minke and George, Sangeeth and Yan, Patrick K. and Kier, Melanie W. and Laughlin, Amy I. and Kothari, Shawn and Giles, Josephine and Mathew, Divij and Ghinnagow, Reem and Alanio, Cecile and Flowers, Ahron and Xu, Wei and Tenney, Daniel J. and Xu, Xiaowei and Amaravadi, Ravi K. and Karakousis, Giorgos C. and Schuchter, Lynn M. and Buggert, Marcus and Oldridge, Derek and Minn, Andy J. and Blank, Christian and Weber, Jeffrey S. and Mitchell, Tara C. and Farwell, Michael D. and Herati, Ramin S. and Huang, Alexander C. (2024) Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8<SUP>+</SUP> T cells. CANCER CELL, 42 (9). ISSN 1535-6108, 1878-3686
Full text not available from this repository. (Request a copy)Abstract
Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8(+) T cells and exhausted CD8(+) T cell (T-EX) clones. Focused analyses of T-EX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor T-EX, which synergizes with anti-PD-1 to reinvigorate T-EX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHRONIC INFECTION; CTLA-4; EFFECTOR; BLOCKADE; PD-1; MELANOMA; IMMUNITY; RECEPTOR; SUBSETS; CD28; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Pädiatrische Hämatologie, Onkologie und Stammzelltransplantation |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Aug 2025 05:49 |
| Last Modified: | 06 Aug 2025 05:49 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65697 |
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