025 Transcriptional profiling of cutaneous immunotoxicity from melanoma immunotherapy

Abstract

Immunotherapy has drastically improved the survival prospect for advanced melanoma. Unfortunately, these treatments often come with cutaneous side effects which may cause the patient to discontinue or delay therapy. To understand the mechanism of cutaneous immunotoxicity in relation to clinical presentation, we characterized cutaneous symptom clusters by clinical and histologic morphology, severity rating, and transcriptional analyses in patients before, during, and after immunotherapy. As of 2020, 30 subjects were recruited, and 12 developed rashes (83% eczematous, 17% psoriasiform) who were treated only with topical steroids. Histologically, 75% demonstrated spongiotic dermatitis; 42% demonstrated a purely lymphocytic infiltrate while only 8% were primarily eosinophilic. Quality of life (QoL) was impacted by the rash, as demonstrated by a score increase on the Skindex, ItchyQoL and ItchyQuant. We next extracted RNA from FFPE punch biopsies to assess the transcriptional differences between baseline prior to therapy, and corresponding normal with rash tissues during immunotherapy. Transcriptional differences between normal tissues at baseline and during therapy, and between different histologic subtypes were not significant, as defined by 2-fold change and FDR<0.05. However, in the rash lesions compared to baseline or corresponding normal tissues, 3140 or 1287 genes, mainly immune-related such as T cell receptor signaling molecules, co-stimulatory receptors, cytotoxic effector molecules, and chemokine receptors, were upregulated, while 1522 or 934 genes corresponding mostly of tight junctional adhesion molecules and lipid syntheses were downregulated. GSEA revealed that rash samples reflected signatures similar to effector and memory CD8 T cells found after vaccination, PD-1 signaling, allograft rejection, and various cytokine signaling pathways. In conclusion, cutaneous immunotoxicity is mediated by pro-inflammatory processes and downregulation of tight junctions and lipid syntheses, which clinically manifests in impact on patient QoL.