Lozano, Chaudhuri, Nene et al. investigated if a baseline immunological state could be identified in metastatic melanoma patients that would predict severe immune-related adverse events (irAEs). CYTOF and single-cell and bulk RNA and TCR sequencing of pretreatment peripheral blood samples from 93 patients, who were subsequently treated with either anti-PD-1 or anti-PD-1/anti-CTLA-4 therapy, showed that increased CD4+ TEM cells and increased TCR diversity were associated with severe irAEs, regardless of the affected organ system or checkpoint inhibitor regimen. Increased peripheral TCR clonal expansion also correlated with earlier onset and severity of irAEs.
Contributed by Katherine Turner
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 Info: (1) Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA. Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. (2) Department of
Author Info: (1) Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA. Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. (2) Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA. aadel@wustl.edu. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. aadel@wustl.edu. Department of Computer Science & Engineering, Washington University, St. Louis, MO, USA. aadel@wustl.edu. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. aadel@wustl.edu. (3) Yale School of Medicine, Yale University, New Haven, CT, USA. (4) Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA. (5) Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA. (6) Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA. (7) Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA. (8) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. (9) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. Department of Biomedical Data Science, Stanford University, Stanford, CA, USA. (10) Stanford Center for Biomedical Informatics Research, Stanford University, Stanford, CA, USA. (11) Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (12) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. (13) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. (14) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. (15) Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA. (16) Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. Division of Dermatology, Washington University School of Medicine, St. Louis, MO, USA. (17) Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA. (18) Department of Medicine, Division of Medical Oncology, Yale University School of Medicine, New Haven, CT, USA. Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA. (19) Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA. Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA. (20) Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA. amnewman@stanford.edu. Department of Biomedical Data Science, Stanford University, Stanford, CA, USA. amnewman@stanford.edu.
