In patients with melanoma who are treated with immune checkpoint inhibitors (ICIs), clonally diverse and activated memory CD4-positive T cells at baseline are associated with the development of severe immune-related adverse events (irAEs), irrespective of the affected organ system. The investigators also explored on-treatment changes in T cell receptor (TCR) clonality among patients receiving combination therapy and linked the findings to the severity and timing of irAE onset. The results are published online on 13 January 2022 by Aaron M. Newman, assistant professor at Stanford University in Stanford, CA, US and colleagues in the Nature Medicine.

The authors wrote in the background that approximately 10%–60% of patients with melanoma treated with ICIs develop severe irAEs which impact a range of organ systems and can be associated with substantial morbidity requiring urgent medical intervention. Such morbidities can lead to the suspension of anticancer treatment and in most severe cases to death. The biological drivers of irAEs are poorly characterised and there is no method in standard clinical practice to identify which patients are at highest risk for their development.

Several groups investigated potential biomarkers of ICI-induced irAEs based on blood or tumour analysis, but these studies have generally been focused on early on-treatment prediction or single organ systems. Recently, a candidate pneumonitis-only irAE biomarker using tumour immunohistochemistry was reported, but it was indirectly identified from The Cancer Genome Atlas, which lacks toxicity annotations, and was evaluated in a case-control setting without the inclusion of low-grade irAEs. Another group identified a single-nucleotide polymorphism within the gene encoding microRNA-146a associated with development of severe irAEs. Other groups have identified ICI response biomarkers without examining irAEs.

Given the considerable heterogeneity of ICI-induced irAEs, including variation in their timing, severity and location, determining the factors of their cause is challenging. Pre-existing autoantibodies, autoreactive tissue-resident T cells and T cells with specificity for viral antigens stemming from chronic viral infection have all been implicated in irAEs. Changes in the gut microbiome leading to increased colonic interleukin-1ß expression were reported in ICI-induced colitis.

Based on these observations, several groups have investigated parallels between irAEs and autoimmune disease. Case reports have shown that ICIs can cause autoimmunity, suggesting that irAEs could represent subclinical autoimmunity in a subset of patients.

However, whether a common baseline immunological state precedes development and distinct manifestations of ICI-induced irAEs is unknown. It prompted the study team to apply mass cytometry by time of flight, single-cell RNA sequencing, single-cell V(D)J sequencing, bulk RNA sequencing and bulk 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 cohorts of 27, 26 and 18 patients, the investigators found that 2 pretreatment factors in circulation, in particular activated CD4 memory T cell abundance and TCR diversity are associated with development of severe irAE regardless of organ system involvement.

The study team also explored on-treatment changes in TCR clonality among patients receiving combination therapy and linked the findings to the severity and timing of irAE onset.

The authors concluded that their results demonstrate circulating T cell characteristics associated with ICI-induced irAEs, with implications for improved diagnostics and clinical management.


Lozano AX, Chaudhuri AA, Nene A, et al. T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma. Nature Medicine; Published online 13 January 2022. DOI: