Faculty Bibliography

The development of immunotherapy has led to a paradigm shift in the treatment of both solid and hematologic malignancies. As immunomodulatory therapies are employed with increasing frequency, a greater number of immune-related adverse reactions are being reported, and the majority of these involve the skin. As a result, dermatologists are increasingly becoming involved in the management of these cutaneous adverse reactions-often providing critical recommendations regarding ongoing cancer treatment. Cutaneous immune-related adverse reactions can vary significantly from patient to patient, making early recognition and timely intervention imperative to mitigate associated morbidity and potential treatment interruption. Although there is considerable overlap in the cutaneous adverse events caused by these immune checkpoint inhibitors, specific eruptions are characteristically associated with particular checkpoint inhibitors. In addition, a patient's comorbidities or immune status can play a significant role in the presentation and management of such adverse reactions. This review characterizes and provides management guidelines for the various cutaneous toxicities associated with checkpoint inhibitor therapy, including CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors. © 2020 Elsevier Inc. All rights reserved.

The advent of immune checkpoint inhibition represents a paradigm shift in the treatment of an increasing number of cancers. However, the incredible therapeutic promise of immunotherapy brings with it the need to understand and manage its diverse array of potential adverse events. The skin is the most common site of immune-related adverse vents (irAEs), which can present with a wide variety of disparate morphologies and severities. These toxicities can endanger patient health and the ability to continue on therapy. This review summarizes our current understanding of the presentation and management of the most common and clinically significant cutaneous irAEs associated with immune checkpoint inhibitor (ICI) therapy. Effective management of these cutaneous irAEs requires an understanding of their morphology, their appropriate clinical characterization, and their potential prognostic significance. Their treatment is additionally complicated by the desire to minimize compromise of the patient's anti-neoplastic regimen and emphasizes the use of non-immunosuppressive interventions whenever possible. However, though cutaneous irAEs represent a challenge to both oncologist and dermatologist alike, they offer a unique glimpse into the mechanisms that underlie not only carcinogenesis, but many primary dermatoses, and may provide clues to the treatment of disease even beyond cancer.

BACKGROUND:There is little evidence to guide surgical management of biopsies yielding the histologic descriptor atypical intraepidermal melanocytic proliferation (AIMP). OBJECTIVE:Determine frequency of and factors associated with melanoma and melanoma in-situ (MIS) diagnoses after excision of AIMP and evaluate margins used to completely excise AIMP. METHODS:Retrospective, cross-sectional study of 1127 biopsies reported as AIMP and subsequently excised within one academic institution. RESULTS:Melanoma (in situ, stage 1A) was diagnosed after excision in 8.2% (92/1127) of AIMP samples. Characteristics associated with melanoma/MIS diagnosis included age 60-79 years (odds ratio [OR] 8.1, 95% confidence interval [CI] 2.5-26.2), age ≥80 years (OR 7.2, 95% CI 1.7-31.5), head/neck location (OR 4.9, 95% CI 3.1-7.7), clinical lesion partially biopsied (OR 11.0, 95% CI 6.7-18.1), and lesion extending to deep biopsy margin (OR 15.1, 95% CI 1.7-136.0). Average ± standard deviation surgical margin used to excise AIMP lesions was 4.5 ± 1.8 mm. LIMITATIONS/CONCLUSIONS:Single-site, retrospective, observational study; interobserver variability across dermatopathologists. CONCLUSION/CONCLUSIONS:Dermatologists and pathologists can endeavor to avoid ambiguous melanocytic designations whenever possible through excisional biopsy technique, interdisciplinary communication, and ancillary studies. In the event of AIMP biopsy, physicians should consider the term a histologic description rather than a diagnosis, and, during surgical planning, use clinicopathologic correlation while bearing in mind factors that might predict true melanoma/MIS.

OBJECTIVE:Plasma high-density lipoproteins have several putative antiatherogenic effects, including preservation of endothelial functions. This is thought to be mediated, in part, by the ability of high-density lipoproteins to promote cholesterol efflux from endothelial cells (ECs). The ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) interact with high-density lipoproteins to promote cholesterol efflux from ECs. To determine the impact of endothelial cholesterol efflux pathways on atherogenesis, we prepared mice with endothelium-specific knockout of Abca1 and Abcg1. APPROACH AND RESULTS:Generation of mice with EC-ABCA1 and ABCG1 deficiency required crossbreeding Abca1(fl/fl)Abcg1(fl/fl)Ldlr(-/-) mice with the Tie2Cre strain, followed by irradiation and transplantation of Abca1(fl/fl)Abcg1(fl/fl) bone marrow to abrogate the effects of macrophage ABCA1 and ABCG1 deficiency induced by Tie2Cre. After 20 to 22 weeks of Western-type diet, both single EC-Abca1 and Abcg1 deficiency increased atherosclerosis in the aortic root and whole aorta. Combined EC-Abca1/g1 deficiency caused a significant further increase in lesion area at both sites. EC-Abca1/g1 deficiency dramatically enhanced macrophage lipid accumulation in the branches of the aorta that are exposed to disturbed blood flow, decreased aortic endothelial NO synthase activity, and increased monocyte infiltration into the atherosclerotic plaque. Abca1/g1 deficiency enhanced lipopolysaccharide-induced inflammatory gene expression in mouse aortic ECs, which was recapitulated by ABCG1 deficiency in human aortic ECs. CONCLUSIONS:These studies provide direct evidence that endothelial cholesterol efflux pathways mediated by ABCA1 and ABCG1 are nonredundant and atheroprotective, reflecting preservation of endothelial NO synthase activity and suppression of endothelial inflammation, especially in regions of disturbed arterial blood flow.

Angiogenesis is regulated by complex interactions between endothelial cells and support cells of the vascular microenvironment, such as tissue myeloid cells and vascular mural cells. Multicellular interactions during angiogenesis are difficult to study in animals and challenging in a reductive setting. We incorporated stromal cells into an established bead-based capillary sprouting assay to develop assays that faithfully reproduce major steps of vessel sprouting and maturation. We observed that macrophages enhance angiogenesis, increasing the number and length of endothelial sprouts, a property we have dubbed "angiotrophism." We found that polarizing macrophages toward a pro-inflammatory profile further increased their angiotrophic stimulation of vessel sprouting, and this increase was dependent on macrophage Notch signaling. To study endothelial/pericyte interactions, we added vascular pericytes directly to the bead-bound endothelial monolayer. These pericytes formed close associations with the endothelial sprouts, causing increased sprout number and vessel caliber. We found that Jagged1 expression and Notch signaling are essential for the growth of both endothelial cells and pericytes and may function in their interaction. We observed that combining endothelial cells with both macrophages and pericytes in the same sprouting assay has multiplicative effects on sprouting. These results significantly improve bead-capillary sprouting assays and provide an enhanced method for modeling interactions between the endothelium and the vascular microenvironment. Achieving this in a reductive in vitro setting represents a significant step toward a better understanding of the cellular elements that contribute to the formation of mature vasculature.

Fixed drug eruption (FDE) is a localized type IV sensitivity reaction to a systemically introduced allergen. It usually occurs as a result of new medication, making identification and avoidance of the trigger medication straightforward; however, in a rare subset of cases no pharmacological source is identified. In such cases, the causative agent is often a food or food additive. In this report we describe a case of a FDE in a 12-year-old girl recently immigrated to the United States from Ecuador who had no medication exposure over the course of her illness. Through an exhaustive patient history and literature review, we were able to hypothesize that her presentation was caused by a dietary change of the natural achiote dye used in the preparation of yellow rice to a locally available commercial dye mix containing tartrazine, or Yellow 5, which has previously been implicated in both systemic hypersensitivity reactions and specifically in FDE. This report adds to the small body of available literature on non-pharmacological fixed hypersensitivity eruptions and illustrates an effective approach to the management of such a presentation when history is not immediately revealing.

UNLABELLED:A proangiogenic role for Jagged (JAG)-dependent activation of NOTCH signaling in the endothelium has yet to be described. Using proteins that encoded different NOTCH1 EGF-like repeats, we identified unique regions of Delta-like ligand (DLL)-class and JAG-class ligand-receptor interactions, and developed NOTCH decoys that function as ligand-specific NOTCH inhibitors. N110-24 decoy blocked JAG1/JAG2-mediated NOTCH1 signaling, angiogenic sprouting in vitro, and retinal angiogenesis, demonstrating that JAG-dependent NOTCH signal activation promotes angiogenesis. In tumors, N110-24 decoy reduced angiogenic sprouting, vessel perfusion, pericyte coverage, and tumor growth. JAG-NOTCH signaling uniquely inhibited expression of antiangiogenic soluble (s) VEGFR1/sFLT1. N11-13 decoy interfered with DLL1-DLL4-mediated NOTCH1 signaling and caused endothelial hypersprouting in vitro, in retinal angiogenesis, and in tumors. Thus, blockade of JAG- or DLL-mediated NOTCH signaling inhibits angiogenesis by distinct mechanisms. JAG-NOTCH signaling positively regulates angiogenesis by suppressing sVEGFR1-sFLT1 and promoting mural-endothelial cell interactions. Blockade of JAG-class ligands represents a novel, viable therapeutic approach to block tumor angiogenesis and growth. SIGNIFICANCE/CONCLUSIONS:This is the first report identifying unique regions of the NOTCH1 extracellular domain that interact with JAG-class and DLL-class ligands. Using this knowledge, we developed therapeutic agents that block JAG-dependent NOTCH signaling and demonstrate for the first time that JAG blockade inhibits experimental tumor growth by targeting tumor angiogenesis.

The Notch signalling pathway is a key regulator of developmental and tumour angiogenesis. Inhibition of Delta-like 4 (Dll4)-mediated Notch signalling results in hyper-sprouting, demonstrating that Notch regulates tip-stalk cell identity in developing tissues and tumours. Paradoxically, Dll4 blockade leads to reduced tumour growth because the newly growing vessels are poorly perfused. To explore the potential for targeting Notch, we developed Notch inhibitors, termed the Notch1 decoys. A Notch1 decoy variant containing all 36 epidermal growth factor (EGF)-like repeats of the extracellular domain of rat Notch1 has been shown to inhibit both Dll and Jagged class Notch ligands. Thus this Notch1 decoy functions differently than Dll4-specific blockade, although it has the potential to inhibit Dll4 activity. Expression of the Notch1 decoy in mice disrupted tumour angiogenesis and inhibited tumour growth. To understand the mechanism by which Notch blockade acts, it is important to note that Notch can function in multiple cell types that make up the vasculature, including endothelial cells and perivascular cells. We investigated Notch function in retinal microglia and determined how myeloid-expressed Notch can influence macrophages and angiogenesis. We found that myeloid-specific loss of Notch1 reduced microglia recruitment and led to improper microglia localization during retinal angiogenesis. Thus either pharmacological inhibition of Notch signalling or genetic deficiencies of Notch function in microglia leads to abnormal angiogenesis.

Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation--features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.