Distinct Immune Signatures Indicative of Treatment Response and Immune-Related Adverse Events in Melanoma Patients under Immune Checkpoint Inhibitor Therapy

Abstract

To identify potential early biomarkers of treatment response and immune-related adverse events (irAE), a pilot immune monitoring study was performed in stage IV melanoma patients by flow cytometric analysis of peripheral blood mononuclear cells (PBMC). Overall, 17 patients were treated with either nivolumab or pembrolizumab alone, or with a combination of nivolumab and ipilimumab every three weeks. Of 15 patients for which complete response assessment was available, treatment responders (n = 10) as compared to non-responders (n = 5) were characterized by enhanced PD-1 expression on CD8+ T cells immediately before treatment (median ± median absolute deviation/MAD 26.7 ± 10.4% vs. 17.2 ± 5.3%). Responders showed a higher T cell responsiveness after T cell receptor ex vivo stimulation as determined by measurement of programmed cell death 1 (PD-1) expression on CD3+ T cells before the second cycle of treatment. The percentage of CD8+ effector memory (CD8+CD45RA−CD45RO+CCR7−) T cells was higher in responders compared to non-responders before and immediately after the first cycle of treatment (median ± MAD 39.2 ± 7.3% vs. 30.5 ± 4.1% and 37.7 ± 4.6 vs. 24.0 ± 6.4). Immune-related adverse events (irAE) were accompanied by a higher percentage of activated CD4+ (CD4+CD38+HLADR+) T cells before the second treatment cycle (median ± MAD 14.9 ± 3.9% vs. 5.3 ± 0.4%). In summary, PBMC immune monitoring of immune-checkpoint inhibition (ICI) treatment in melanoma appears to be a promising approach to identify early markers of treatment response and irAEs.

Peripheral T cell cytotoxicity predicts the efficacy of anti-PD-1 therapy for advanced non-small cell lung cancer patients

“…The significance of monitoring the CD45RA+CD25+/CD4+ T cell ratio during anti-PD-1 therapy needs to be elucidated. On the other hand, a higher percentage of activated peripheral CD4+ T cells was detected in patients with irAEs before the second treatment cycle of ICIs 28 . The frequency of peripheral cytotoxic CD4+ T cells was shown to correlate with destructive thyroiditis induced by anti-PD-1 therapy 29 .…”

Peripheral absolute eosinophil count identifies the risk of serious immune-related adverse events in non-small cell lung cancer

“…However, we make reference to the fact that Reschke et al. used flow cytometry to examine peripheral blood samples from melanoma patients receiving ICIs and discovered that PD-1 downregulation had the greatest impact on CD3+, CD4+, and CD8+ T cells at all time points after treatment initiation and that CD8+CD38+ T cells and CD8+ effector memory T cells were higher at the time point of AEs ( 47 ). Kotwal et al.…”

“…events. and that CD8+CD38+ T cells and CD8+ effector memory T cells were higher at the time point of AEs(47). Kotwal et al compared 10 patients with ICIs-induced thyroiditis with healthy thyroid samples (n=5) by flow cytometry of thyroid fine needle aspirates and found a significant increase of CD8+ T lymphocytes in the thyroid gland of patients with ICIs-induced thyroiditis(48).…”

A Novel Potential Role for Monocytes Revealed by Single Cell Analysis of Immunotherapy Induced Immune Related Adverse Events

“…One study has identified a decrease in TEM cell populations among patients who developed irAEs although only a significant drop among CD4 + TEM cells was observed [ 10 ]. Another group recently found that circulating TEM (both CD4 and CD8) trended down in patients that developed irAE, while the opposite was true in patients whose tumors responded to their therapy [ 11 ]. Additional work is needed to determine whether these disparate patterns represent mechanistic differences between the irAE developing in different organ systems, between different patient contexts, or an alternative explanation is responsible.…”