Journal Article

T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma

Nene, Aishwarya, Lozano, Alexander X., Halaban, Ruth, Vahid, Milad R., Steen, Chloé B., Usmani, Abul, Sznol, Mario, Badri, Ti, Chen, David Y., Turner, Brandon E., Earland, Noah, Dhodapkar, Kavita, Luca, Bogdan A., Gulati, Gunsagar S., Bacchiocchi, Antonietta, Khameneh, Farnaz, Newman, Aaron M., Harris, Peter K., Vesely, Matthew D., Chaudhuri, Aadel A.

2022

Overview

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. Clonally diverse and activated memory CD4 + T cells at baseline are associated with the development of severe immune-related adverse events, irrespective of the affected organ system, in patients with melanoma treated with immune checkpoint inhibitors.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/114/2397 / 631/61/212/2166 / 631/67/1059/2325 / 631/67/1813/1634 / Adverse events / Biomedical and Life Sciences / Biomedicine / Blood / Cancer Research / CD4 antigen / CTLA-4 protein / Cytometry / Gene sequencing / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - adverse effects / Immunological memory / Immunology / Infectious Diseases / Inhibitors / Lymphocytes / Lymphocytes T / Melanoma / Melanoma - drug therapy / Memory cells / Metabolic Diseases / Molecular Medicine / Neurosciences / Patients / PD-1 protein / Peripheral blood / Retrospective Studies / T cell receptors / T-Lymphocytes / Toxicity