Hanna Terhaar

Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, and other signaling pathways. We explore the interplay between innate and adaptive immunity in the TME and tumor intrinsic resistance mechanisms, such as β-catenin, which has future implications for the usage of ICIs in patients with therapy-resistant tumors. Methods: A total of 1052 studies were extracted from the PubMed database searching for keywords and phrases that included [melanoma AND immune checkpoint inhibitor resistance]. After a title/abstract and full-text review, 101 studies were identified that fit the inclusion/exclusion criteria. Results: Cancer-associated fibroblasts (CAFs), M2 macrophages, and myeloid-derived suppressor cells (MDSCs) are significant in remodeling the TME to promote melanoma growth. Melanoma resistance to ICIs is complex and involves TME alterations, tumor intrinsic factors, and immune evasion. Key components of resistance include reduced CD8+ T cell infiltration, decreased host immune response, and immunosuppressive cytokines. Conclusions: Predictive biomarkers and specific models are the future of individualized melanoma management and show great promise in their approach to targeted therapy production. Tumor profiling can be utilized to help predict the efficacy of ICIs, and specific biomarkers predicting therapy responses are instrumental in moving towards personalized and more efficacious medicine. As more melanoma resistance emerges, alternative and combinatorial therapy based on knowledge of existing resistance mechanisms will be needed.

Introduction: Studies on the association between immune-mediated disorders and lymphoid disorders have been very limited, especially in diverse populations. The objective of this study is to evaluate the relationship between a variety of immune diseases and lymphoid malignancies. Methods: The NIH “All of Us” database was utilized to perform a cross-sectional analysis between lymphoid disorders and various immune diseases. The adjusted multivariable logistic regression analysis was performed in R to examine the association between lymphoid disorders such as leukemia, lymphoma, and plasma cell neoplasms against a variety of autoimmune diseases. Results: In the study cohort of 316,044 patients, we found significant associations between lymphomas and the aforementioned immune-mediated diseases, with the exception of dermatomyositis and scleroderma. Lymphoid leukemias showed significant associations (p < 0.001) with several autoimmune conditions, including psoriasis, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, and hyperthyroidism. In plasma cell neoplasms, significant associations were found in all but dermatomyositis, scleroderma, vitiligo, and atopic dermatitis (p < 0.001). Conclusions: In this population-level analysis, the majority of immune-mediated diseases were found to be significantly correlated with an increased incidence of lymphoid malignancies. As such, patients diagnosed with immune-mediated diseases should undergo close surveillance and early screening with the goal of early identification and treatment of lymphoid malignancies.

The immune repertoire (IR) is a term that defines the combined unique genetic rearrangements of antigen receptors expressed by B and T lymphocytes. The IR determines the ability of the immune system to identify and respond to foreign antigens while preserving tolerance to host antigens. When immune tolerance is disrupted, development of autoimmune diseases can occur due to the attack of self-antigens. Recent technical advances in immune profiling allowed identification of common patterns and shared antigen-binding sequences unique to diverse array of diseases. However, there is no current literature to date evaluates IR findings in autoimmune and skin inflammatory conditions. In this review, we provide an overview of the past and current research findings of IR in various autoimmune and dermatologic conditions. Enriching our understanding of IRs in these conditions is critical for understanding the pathophysiology behind autoimmune skin disease onset and progression. Furthermore, understanding B-cell and T-cell IR will help devise therapeutic treatments in the hopes of restoring immune tolerance and preventing disease onset and progression.

Extracorporeal photopheresis (ECP) is an apheresis procedure that is conventionally used as a first-line treatment for cutaneous and leukemic subtypes of T-cell lymphoma, such as Sezary’s syndrome and mycosis fungoides. Over the past three decades, its immunotherapeutic properties have been tested on a variety of autoimmune conditions, including many dermatologic diseases. There is ample evidence of ECP’s ability to modify leukocytes and alter cytokine production for certain dermatologic diseases that have been refractory to first-line treatments, such as atopic dermatitis. However, the evidence on the efficacy of ECP for the treatment of these dermatologic diseases is unclear and/or lacks sufficient evidence. The purpose of this paper is to review the literature on the utilization and clinical efficacy of ECP in the treatment of several [autoimmune] dermatologic diseases and discuss its applications, guidelines, recommendations, and future implementation for dermatologic diseases.

Morbidity and mortality from skin cancer continue to rise domestically and globally, and melanoma and non-melanoma skin cancers are a topic of interest in the dermatology and oncology communities. In this review, we summarize the stimulator of interferon genes (STING) pathway, its specific role in the pathogenesis of DNA damage and skin cancer, and STING-specific therapies that may fight both melanoma and non-melanoma skin (NMSC) cancers. Furthermore, we discuss specific portions of the STING pathway that may be used in addition to previously used therapies to provide a synergistic effect in future oncology treatments and discuss the limitations of current STING-based therapies.