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Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles
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Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles
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Journal Article
Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles
2021
Overview
Background
Immune checkpoint blockers (ICBs) activate CD8
+
T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.
Methods
Retrospective evaluation of irAEs on survival was performed across primary (
N
= 144) and secondary (
N
= 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8
+
T cells was sequenced and differential gene expression according to irAE development assessed.
Results
58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS:
P
< 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (
P
= 2.8 × 10
−6
). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8
+
T cells according to irAE development, and patients not developing irAEs demonstrating upregulated
CXCR1
pre- and post-treatment.
Conclusions
Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Aged
/ Antineoplastic Agents, Immunological - adverse effects
/ Antineoplastic Agents, Immunological - therapeutic use
/ Autoimmune Diseases - chemically induced
/ Autoimmune Diseases - diagnosis
/ Autoimmune Diseases - epidemiology
/ Autoimmune Diseases - genetics
/ Biomedical and Life Sciences
/ CD8-Positive T-Lymphocytes - drug effects
/ CD8-Positive T-Lymphocytes - metabolism
/ CD8-Positive T-Lymphocytes - pathology
/ Female
/ Gene Expression Regulation, Neoplastic - drug effects
/ Humans
/ Immune Checkpoint Inhibitors - adverse effects
/ Immune Checkpoint Inhibitors - therapeutic use
/ Immunotherapy - adverse effects
/ Male
/ Melanoma
/ Oncology
/ Patients
/ Skin Neoplasms - drug therapy
