@article{73e32207eace4312a28d7aea62d65f8a,
title = "T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma",
abstract = "Severe immune-related adverse events (irAEs) occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). However, it is unknown whether a common baseline immunological state precedes irAE development. Here we applied mass cytometry by time of flight, single-cell RNA sequencing, single-cell V(D)J sequencing, bulk RNA sequencing and bulk T cell receptor (TCR) sequencing to study peripheral blood samples from patients with melanoma treated with anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combination ICIs. By analyzing 93 pre- and early on-ICI blood samples and 3 patient cohorts (n = 27, 26 and 18), we found that 2 pretreatment factors in circulation—activated CD4 memory T cell abundance and TCR diversity—are associated with severe irAE development regardless of organ system involvement. We also explored on-treatment changes in TCR clonality among patients receiving combination therapy and linked our findings to the severity and timing of irAE onset. These results demonstrate circulating T cell characteristics associated with ICI-induced toxicity, with implications for improved diagnostics and clinical management.",
author = "Lozano, {Alexander X.} and Chaudhuri, {Aadel A.} and Aishwarya Nene and Antonietta Bacchiocchi and Noah Earland and Vesely, {Matthew D.} and Abul Usmani and Turner, {Brandon E.} and Steen, {Chlo{\'e} B.} and Luca, {Bogdan A.} and Ti Badri and Gulati, {Gunsagar S.} and Vahid, {Milad R.} and Farnaz Khameneh and Harris, {Peter K.} and Chen, {David Y.} and Kavita Dhodapkar and Mario Sznol and Ruth Halaban and Newman, {Aaron M.}",
note = "Funding Information: We thank the patients and families involved in this study. We thank A. Nassar and L. Chen for technical assistance with the CyTOF experiments, including provision of resources, staining and processing of samples. We thank G. Ansstas and C. Kaufman for clinical samples. We also thank T. Ley, S. Devarakonda and M. Tal for providing critical feedback on the manuscript. This work was supported by grants from the National Cancer Institute (no. K08CA238711 to A.A.C., no. K08CA237727 to D.Y.C., no. R01CA238471 to K.D., no. R21CA218950 to R.H. and no. R00CA187192 to A.M.N.), National Heart, Lung, and Blood Institute (no. T35HL007649 to A.N.), National Institute of Arthritis and Musculoskeletal and Skin Diseases (no. R01AR077926 to K.D.), a fellowship from the Natural Sciences and Engineering Research Council of Canada (A.X.L.), the Cancer Research Foundation Young Investigator Award (A.A.C.), V Foundation for Cancer Research V Scholar Award (A.A.C.), Washington University Alvin J. Siteman Cancer Research Fund (A.A.C.), Yale Cancer Center Meyers Award (M.S. and R.H.), a 10x Genomics Pilot Program Award (R.H.), the Melanoma Research Alliance (no. 137453 and no. 828544 to R.H.), the Virginia and D.K. Ludwig Fund for Cancer Research (A.M.N.), Stinehart-Reed Foundation (A.M.N.), Stanford Bio-X Interdisciplinary Initiatives Seed Grants Program (IIP) (A.M.N.) and Donald E. and Delia B. Baxter Foundation (A.M.N.). Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = feb,
doi = "10.1038/s41591-021-01623-z",
language = "English",
volume = "28",
pages = "353--362",
journal = "Nature Medicine",
issn = "1078-8956",
number = "2",
}