Immunologic profiling of immune-related cutaneous adverse events with checkpoint inhibitors reveals polarized actionable pathways Journal Article
| Authors: | Lacouture, M. E.; Goleva, E.; Shah, N.; Rotemberg, V.; Kraehenbuehl, L.; Ketosugbo, K. F.; Merghoub, T.; Maier, T.; Bang, A.; Gu, S.; Salvador, T.; Moy, A. P.; Lyubchenko, T.; Xiao, O.; Hall, C. F.; Berdyshev, E.; Crooks, J.; Weight, R.; Kern, J. A.; Leung, D. Y. M. |
| Article Title: | Immunologic profiling of immune-related cutaneous adverse events with checkpoint inhibitors reveals polarized actionable pathways |
| Abstract: | 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. © 2024 The Authors. |
| Keywords: | adult; controlled study; human tissue; aged; major clinical study; histopathology; skin biopsy; interleukin 13; interleukin 4; interleukin 5; enzyme linked immunosorbent assay; psoriasis; self report; questionnaire; maculopapular rash; t cell lymphoma; regulatory t lymphocyte; gamma interferon; messenger rna; blood analysis; interleukin 6; cytokine production; immunophenotyping; real time polymerase chain reaction; upregulation; lymphocytic infiltration; lymphocyte; urticaria; immunofluorescence microscopy; immunoglobulin e; vitiligo; eosinophil count; patient-reported outcome; bullous dermatitis; eczema; lichenoid; human; male; female; article; urine sampling; checkpoint inhibitor therapy; interleukin 31 |
| Journal Title: | Clinical Cancer Research |
| Volume: | 30 |
| Issue: | 13 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-07-01 |
| Start Page: | 2822 |
| End Page: | 2834 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-23-3431 |
| PUBMED: | 38652814 |
| PROVIDER: | scopus |
| PMCID: | PMC11215405 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF -- Source: Scopus |
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