Research

The advent of targeting immune inhibitory receptors, or “immune checkpoints,” has heralded a new era in oncology, referred to as immuno-oncology. Most notable is blockade of programmed death 1 receptor (PD-1) or its ligand PD-L1 that is FDA-approved for cutaneous malignancies: melanoma, basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC). Despite these advances, many patients fail to respond to anti-PD-1/PD-L1 immunotherapy. Focusing on melanoma and cSCC, we use human patient samples to decipher the mechanisms of immunotherapy resistance in close collaboration with the laboratory of Lieping Chen MD, PhD. Specifically, we focus on other immune inhibitory receptors such as programmed death 1 homolog (PD-1H) (also known as VISTA) as a potential mechanism of acquired immune resistance in melanomas and cSCCs. Several anti-PD-1H/VISTA therapeutics are in early clinical stage development for the treatment of cancers. It is our goal to identify subsets of patients with cutaneous malignancies that may be benefit from this potential new immunotherapy.

As immune checkpoint blockade cancer immunotherapy has led to significant clinical benefit, it has also unleashed autoimmunity in many patients that often limits effective anti-cancer immunotherapy. These cutaneous immune-related adverse events (cirAEs) are often associated with better outcomes, suggesting that invigoration of the immune system to effectively attack cancer also results in immune attack of one’s own skin. We examine the pathobiology of specific cirAEs and the corollary anti-cancer immune response using human patient samples and the latest technological tools such as single cell spatial proteomics and transcriptomics. Our goal is to determine whether autoimmune skin disease because of an immunotherapy cirAE shares key immune pathways with de novo autoimmune skin diseases that occur in the absence of cancer immunotherapy. We also intend to identify therapeutic targets of cirAEs so that cancer patients who develop cirAES can be treated for autoimmunity without impacting cancer immunotherapy.

Immune attack of the dermal-epidermal junction (DEJ) results in many different autoimmune diseases broadly defined as interface dermatoses. Interface dermatoses can be further refined as either vacuolar or lichenoid interface dermatoses based on histological patterns of the immune infiltrate. We study archetypal examples of vacuolar (cutaneous lupus erythematosus) and lichenoid (lichen planus) interface dermatoses to better understand the inflammatory pathways and the cellular interactions involved that lead to distinct immune cell composition and architecture. Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin disease that severely impairs quality of life and is characterized by disfiguring scarring, hair loss, itching, and pain. It can also be associated with systemic lupus erythematosus. Lichen planus (LP) is a chronic mucocutaneous disease that involves pruritic skin lesions and painful mucosal sores. Both CLE and LP lack FDA-approved therapies and current treatments are not always effective in the most severe cases. In addition to studying these diseases in the lab, Dr. Vesely also specializes in the treatment of these patients in his dermatology clinic.

Current advances in treating cutaneous autoimmune diseases have predominately been achieved through the blockade of cytokines, soluble chemical messengers between cells, their receptors or downstream cellular signaling pathways. This approach can effectively treat ongoing inflammation but requires continual usage. An emerging potential therapeutic strategy is targeting immune inhibitory receptors, immune checkpoints, to “reset” or induce immune tolerance for longer disease remissions. Many immune checkpoint agonists are in development for the treatment of autoimmunity. Our goal is to identify which immune checkpoint should be rationally targeted in a specific inflammatory skin diseases or disease subset. Our research focuses on PD-1H (VISTA) agonist therapy for multiple inflammatory skin diseases, including cutaneous lupus erythematosus.