Linking T Cell Traits to Immune Therapy Side Effects in Melanoma
Summary
Pervasive immunological-related adverse events (irAEs) manifest in approximately 60% of melanoma-afflicted patients undergoing treatment with immune checkpoint inhibitors (ICIs). Nevertheless, the existence of a shared preliminary immunological state antecedent to the development of irAEs remains an enigma. In this investigation, the researchers employed 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 methodologies to scrutinize peripheral blood specimens derived from melanoma patients subjected to anti-PD-1 monotherapy or the concomitant administration of anti-PD-1 and anti-CTLA-4 ICIs. Upon examination of 93 pre- and early on-ICI blood specimens, as well as three distinct patient cohorts (n = 27, 26, and 18), the investigators unveiled that two antecedent factors within the circulatory system—elevated levels of activated CD4 memory T cells and TCR diversity—correlate with the development of severe irAEs, irrespective of the organ system affected. Moreover, they delved into alterations in TCR clonality during treatment amongst patients undergoing combined therapy, subsequently associating their discoveries with the severity and chronology of irAE emergence. These findings unveil the circulating T cell attributes implicated in ICI-induced toxicity, bearing consequential implications for the enhancement of diagnostic techniques and the administration of clinical management.
Research Criteria
Immunological-related adverse events (irAEs) are common in roughly 60% of melanoma patients receiving immune checkpoint inhibitor treatment (ICIs). Yet, the existence of a shared early immunological condition preceding the genesis of irAEs remains a mystery. In this study, the researchers used time of flight mass cytometry, single-cell RNA sequencing, single-cell V(D)J sequencing, bulk RNA sequencing, and bulk T cell receptor (TCR) sequencing to examine peripheral blood specimens from melanoma patients who received anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 ICIs concurrently.
Fig.1 Experimental design. (Lozano, 2022)
Sample Type
Human blood samples.
Result—Determinants of Severe irAEs from Pretreatment Blood
They analyzed peripheral blood specimens from 13 patients, utilizing 5' droplet-based 10x scRNA-seq in tandem with single-cell immune profiling of TCR and BCR clonotypes. Through unsupervised clustering, they discerned 32 unique transcriptional states spanning seven cell types and assessed correlations with severe irAE development. Subsequent analyses unveiled CD4 T cell state 3, intimately related to state 5, exhibited a CD4 TEM expression profile. Differential gene expression comparisons revealed CD4 T states 5 and 3 as enriched with activated effector cell markers. Augmented single-cell TCR clonotype diversity in activated CD4 T states 5 and 3 correlated with severe irAEs, suggesting a more heterogeneous baseline TCR repertoire in CD4 TEM cells, mirrored in peripheral blood, is linked to pronounced ICI toxicity.
Fig.2 Analysis of pretreatment peripheral blood for cellular determinants of severe irAEs using single cell RNA and V(D)J sequencing. (Lozano, 2022)
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Reference
- Lozano, A.X.; et al. T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma. Nature Medicine. 2022, 28(2): 353-362.
