Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma

 

Highlights

  • Single-cell RNA-seq reveals distinct CD45+ cells associated with clinical outcome
  • The balance between two CD8+ T cell states is linked with tumor regression
  • TCF7+CD8+ T cell frequency in tumor tissue predicts response and better survival
  • Dual blockade of CD39 with different checkpoint proteins enhances immunity

 

Authors

Moshe Sade-Feldman,1,2,3,14 Keren Yizhak,2,14 Stacey L. Bjorgaard,1,2 John P. Ray,2 Carl G. de Boer,2
Russell W. Jenkins,1,3,4 David J. Lieb,2 Jonathan H. Chen,2,5 Dennie T. Frederick,1 Michal Barzily-Rokni,1 Samuel S. Freeman,2,6 Alexandre Reuben,7 Paul J. Hoover,2,8 Alexandra-Chloe ́ Villani,1,2,3 Elena Ivanova,3,9 Andrew Portell,3,9 Patrick H. Lizotte,3,9 Amir R. Aref,3,9 Jean-Pierre Eliane,5 Marc R. Hammond,1 Hans Vitzthum,1 Shauna M. Blackmon,1 Bo Li,2,10 Vancheswaran Gopalakrishnan,7 Sangeetha M. Reddy,7 Zachary A. Cooper,7,11 Cloud P. Paweletz,3,9 David A. Barbie,3 Anat Stemmer-Rachamimov,5 Keith T. Flaherty,1,3 Jennifer A. Wargo,7,11 Genevieve M. Boland,1,12 Ryan J. Sullivan,1,3 Gad Getz,1,2,5,13,* and Nir Hacohen1,2,3,15,*


1 Massachusetts General Hospital Cancer Center, Harvard Medical School (HMS), Boston, MA, USA
2 Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA
3 Department of Medicine, Massachusetts General Hospital, HMS, Boston, MA, USA
4 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
5 Department of Pathology, Massachusetts General Hospital, HMS, Boston, MA, USA
6 Department of Biomedical Informatics, HMS, Boston, MA, USA
7 Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
8 Brigham & Women’s Hospital, Division of Rheumatology, Immunology and Allergy, Boston, MA, USA
9 Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA, USA
10 Department of Virology, Harvard Medical School, Boston, MA, USA
11 Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
12 Department of Surgery, Massachusetts General Hospital, HMS, Boston, MA, USA
13 Department of Pathology, Harvard Medical School, Boston, MA, USA
14 These authors contributed equally
15 Lead Contact
*Correspondence: gadgetz@broadinstitute.org (G.G.), nhacohen@mgh.harvard.edu (N.H.)

https://doi.org/10.1016/j.cell.2018.10.038

 

Summary

Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors. Two distinct states of CD8+ T cells were defined by clustering and associated with patient tumor regression or progression. A single transcription factor, TCF7, was visualized within CD8+ T cells in fixed tumor samples and predicted positive clinical outcome in an independent cohort of checkpoint-treated patients. We delineated the epigenetic landscape and clonality of these T cell states and demonstrated enhanced antitumor immunity by targeting novel combinations of factors in exhausted cells. Our study of immune cell transcriptomes from tumors demonstrates a strategy for identifying predictors, mechanisms, and targets for enhancing checkpoint immunotherapy.