作者
Kevin Wang,Paulina Coutifaris,David Brocks,Guanning Wang,Tarek Azar,Sabrina Solis,Ajeya Nandi,S. Keith Anderson,Nicholas Han,Sasikanth Manne,Evgeny Kiner,Chirag Sachar,Mairi Lucas,Sangeeth M. George,Patrick Yan,Melanie Wain Kier,Amy Iarrobino Laughlin,Shawn Kothari,Josephine R. Giles,Divij Mathew,Reem Ghinnagow,Cécile Alanio,Ahron Flowers,Wei Xu,Daniel J. Tenney,Xiaowei Xu,Ravi K. Amaravadi,Giorgos C. Karakousis,Lynn M. Schuchter,Marcus Buggert,Derek A. Oldridge,Andy J. Minn,Christian U. Blank,Jeffrey S. Weber,Tara C. Mitchell,Michael D. Farwell,Ramin S. Herati,Alexander C. Huang
摘要
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