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Published on: February 5, 2020
Immunologic Profiling of Immune-Related Cutaneous Adverse Events with Checkpoint Inhibitors Reveals Polarized
Mario E Lacouture1, Elena Goleva2, Neil Shah3
1Dermatology Service, Division of Subspecialty Medicine, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Insights
Immune-related skin reactions to checkpoint inhibitors have distinct immune profiles. Identifying these endotypes can guide precision medicine for better treatment outcomes.
Area of Science:
- Dermatology
- Immunology
- Oncology
Background:
- Immune-related cutaneous adverse events (ircAEs) affect over 50% of patients on checkpoint inhibitors.
- The underlying mechanisms of ircAEs remain poorly understood, hindering effective management.
Purpose of the Study:
- To characterize the clinical presentation and immunologic endotypes of ircAEs.
- To identify distinct cytokine profiles associated with specific ircAE phenotypes.
Main Methods:
- Phenotyping and biomarker analyses were performed on 200 patients receiving checkpoint inhibitors.
- Cytokine levels were measured in skin biopsies, tape strips, and plasma using real-time PCR and multiplex assays.
Main Results:
- Eight distinct ircAE phenotypes were identified, including maculopapular rash, eczema, and lichenoid dermatitis, all showing skin lymphocyte and eosinophil infiltrates.
- Specific cytokine profiles correlated with phenotypes: IFNγ in lichenoid/psoriasiform, IL13 in eczema, and IL17A in psoriasiform/lichenoid/bullous dermatitis/MPR.
- Distinct cytokine patterns were observed across skin and plasma, with type 1/17 pathway activation in psoriasiform, lichenoid, bullous dermatitis, and vitiligo.
Conclusions:
- Distinct immunologic endotypes of ircAEs were identified.
- These findings suggest potential actionable targets for precision medicine interventions in managing ircAEs.
Purpose:
Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood.
Experimental Design:
Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays.
Results:
Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P < 0.0001) and psoriasiform dermatitis (P < 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P < 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P < 0.001), lichenoid (P < 0.0001), bullous dermatitis (P < 0.05), and MPR (P < 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine-targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo.
Conclusions:
Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions.
