Anisha B. Patel

Immune checkpoint inhibitor-induced lichen planus (ICI-LP) is a cutaneous immune related adverse event (irAE) that shares key clinicopathologic features with spontaneous lichen planus (LP) but differs histologically and in the sex distribution of its incidence, and may therefore reflect a distinct tissue inflammatory state. To define the cellular programs that distinguish ICI-LP from LP, we profiled lesional skin by single cell and spatial transcriptomic approaches. We found few differences in the T cell and keratinocyte compartments between ICI-LP and LP, which shared similar inflammatory signatures. Rather, the dominant transcriptional features differentiating these two eruptions occurred within the fibroblast and myeloid cell compartments. Fibroblasts in ICI-LP were enriched for IGF1, FGF7, and androgen-response-associated programs, whereas myeloid cells exhibited amplified JAK-STAT and interferon-responsive states spanning both type I and type II interferon signatures. The potential role of androgen response in shaping lichenoid inflammation was supported by a striking loss of androgen receptor expression in lesional keratinocytes by immunohistochemistry. Furthermore, using spatial RNA and transcriptomic approaches, we identified anatomically segregated IFNG, IL17A , and IL13 niches within lesional skin, suggesting that regional immune compartmentalization with differences in local immunoregulation may explain the mixed inflammatory features reported in both ICI-LP and LP. Collectively, these data indicate that ICI-LP is not simply a more inflamed form of LP, but a distinct form of the disease with more prominent inflammatory perturbations within stromal and innate immune cell populations.

Background: While immune checkpoint inhibitors (ICIs) have shown significant efficacy, a common side effect is cutaneous immune‐related adverse events (irAEs). This study focuses on exploring the association between specific human leukocyte antigen (HLA) alleles and the development of cutaneous irAEs in melanoma patients undergoing ICI monotherapy and combination therapy. As certain HLA types are indicative of susceptibility to autoimmune diseases, it was hypothesized that HLA typing could serve as a potential screening tool for identifying patients at increased risk for developing irAEs. Methods: A retrospective chart review was performed of 515 patients with melanoma who underwent ICI therapy, either as monotherapy or in combination, and had HLA typing available. This analysis spans from 2003 to 2023 with a focus on cutaneous irAEs. Statistical analyses were conducted to assess the association between HLA alleles and irAEs. Results: Our analysis revealed that the HLA‐B*51:01 allele was associated with a higher risk of cutaneous irAEs after adjusting for ICI regimen (hazard ratio: 1.71 [95% CI, 1.12–2.61], p = .013.) Conclusion: This is the largest study to link an HLA allele with ICI‐induced cutaneous irAEs. The findings may support the use of HLA typing as an initial screen for developing irAEs, providing a simple, straightforward metric that can be rapidly performed on patients prior to initiation of ICIs. However, further research is needed across different cancer and toxicity types.

Supplementary Table from Phase I Dose Escalation Study of Topical Bexarotene in Women at High Risk for Breast Cancer

Supplementary Table 1: All Adverse Events related to topical 1% bexarotene gel.

Background: Although immune checkpoint inhibitors (ICIs) are efficacious, they often cause immune-related adverse events (irAEs), most commonly cutaneous irAEs (CirAEs). The mechanisms underlying CirAEs remain unclear. Methods: Attempting to better understand their mechanisms and histology we conducted a prospective study of 15 patients with advanced cancers treated with ICIs who developed grade 2 or higher CirAEs. Clinical and histologic characterization of biopsy specimens of CirAEs was performed. Histologic analysis of patient biopsy specimens were subdivided by epidermal reaction patterns that included spongiotic, lichenoid, and interface dermatitis patterns. A targeted RNA expression assay was used to identify immune markers in CirAE lesions and adjacent unaffected skin samples. Conclusions: Compared with adjacent unaffected skin, CirAE lesions had significantly upregulated THY1 (CD90) and increased M2 macrophages (adjusted pTHY1 and elevated numbers of M2 macrophages in CirAE lesions suggest THY1 and M2 macrophages may be involved in the pathogenesis of these toxic effects. Further investigation to elucidate the molecular determinants of CirAEs and develop targeted therapeutic strategies is warranted.

Purpose Epidermal growth factor receptor inhibitors (EGFRIs) and immune checkpoint inhibitors (ICIs) show promising efficacy in colorectal cancer and head and neck squamous cell carcinoma therapy, especially in combination. However, given the many cutaneous adverse effects (CAE) associated with each, there is concern for overlap and exacerbation of toxicities. EGFRIs are associated with acneiform rashes and paronychia, while ICIs are associated with lichenoid dermatitis and psoriasis. Xerosis, pruritus, and eczema are seen with both drugs. Understanding the CAEs of EGFRI-ICI combination therapy may guide the management of toxicities and improve adherence to life-saving therapy. Methods A retrospective chart review of patients treated with EGFRI/ICI combination between January 1, 2015, and May 21, 2024, was performed. Data on demographics, cancer type, and CAE incidence, duration, and management were manually investigated. Results Forty-four patients were identified on EGFRI/ICI therapy, with 26 patients (59%) developing a total of 42 CAEs. Patients received cetuximab-pembrolizumab (72%) or cetuximab-nivolumab (28%) therapy. The most common CAEs seen were acneiform eruption (33%) and eczema (18%). Most CAEs were caused by EGFRI (62%) with 12% attributable to ICI, and 24% of CAEs attributed to either/both drugs. Most CAEs were reported as mild to moderate. Conclusion Combination EGFRI/ICI therapy is quickly becoming standard treatment in certain cancers, and the incidence of CAEs is high (59%) in this population. CAEs appear to be skewed towards EGFRI rashes and low-grade severity. A prospective trial is warranted to further understand the impact of CAEs for patients being treated with this combination therapy.