Jeffrey A. Kern

Background: Immune‐related cutaneous adverse events (ircAEs) complicate management in many cancer patients receiving checkpoint inhibitor (CPI) immunotherapy. A new approach to early prognosis and ircAE treatment monitoring is needed in order to improve patient adherence to CPI immunotherapy. Methods: Skin tape strips (STS) and plasma were collected prospectively from 22 oncology patients prior to starting CPI and after 6 weeks of CPI therapy. Patients were then followed for ircAE development for 6 months. Ten patients subsequently developed ircAEs. STS were analyzed for cytokines and lipids, while plasma was analyzed for cytokines. Results: A significant increase in stratum corneum (SC) ceramides with short chain fatty acids was observed in patients who developed ircAEs ( p < 0.05 compared to non‐ircAE groups). This lipid abnormality was already present in the skin of future ircAE patients before starting CPI immunotherapy, and was further dysregulated on CPI therapy. Following CPI initiation, significant increases in skin (but not plasma) IL‐8, IL‐18, and IP‐10 (CXCL10), IL‐12, IFNa, MDC (CCL22), and TARC (CCL17) production were observed in patients who subsequently developed ircAEs ( p < 0.05 compared to non‐ircAE groups). Conclusion: STS analysis of patients developing ircAEs demonstrated SC lipid abnormalities prior to CPI treatment. When studied after 6 weeks of CPI therapy, these SC barrier lipid abnormalities were worsened. In addition, significant increases in proinflammatory cytokine levels were identified in the skin, but not in plasma. These findings point to mechanisms of ircAE development and may allow early identification of patients at risk of developing ircAEs for close monitoring and future prevention of treatment‐limiting ircAEs.

Supplementary Figure S4. Levels of pro-inflammatory mediators, chemokines, and alarmins in the skin tape strip (STS) and plasma samples of patients with cancer experiencing checkpoint inhibitor induced immune-related cutaneous adverse events (ircAEs).

Supplementary Table S3. Cancer types and stages of study participants.

Supplementary Table S2. Demographics of study participants.

Supplementary Table S5. Checkpoint inhibitor (CPI) classes and therapeutic combinations received by study participants.

Supplementary Table S1. Key resources—multiplex cytokine assays.

Supplementary Table S4. Cancer types and stages of study participants by immune-related cutaneous adverse event (ircAE) phenotype.

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.

Supplementary Figure S2. Peripheral blood differential cell counts assessment of patients with cancer experiencing checkpoint inhibitor induced immune-related cutaneous adverse events (ircAE).