Despite the advancements in immunotherapies for cancer having profound impact on survival for some patients, the lack of consistent, predictive markers of treatment response and adverse event risk remains a significant clinical challenge. Checkpoint inhibitors targeting programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and other immune checkpoints, have significantly altered the landscape of melanoma care, but a substantial portion of patients still face inadequate responses, underscoring the critical need for improved biomarker tools that offer high distinguishability, single to subcellular resolution, and high throughput with low-cost preparation. The work presented here focuses on the imperative need for precision medicine in cancer treatment, particularly to resolve the complexities in harnessing the immune system's potential for therapeutic benefits. The diverse and heterogeneous nature of melanoma, characterized by high mutational burden and adaptive resistance mechanisms, complicates the identification of effective biomarkers for best treatment selection. One focus of this research lies in exploring neoadjuvant intra-tumoral therapy in high-risk melanoma, revealing promising results in generating systemic immune responses with less severe adverse event profiles compared to systemic treatments, such as immune checkpoint blockade (ICB). Studying the immune cell dynamics related to therapy responses has identified potential novel markers that shed critical light on the inconsistencies of patient responses and the importance of innate immune cell contributions. Novel technical approaches incorporating immune time-resolved Förster resonance energy transfer (iFRET) technology are utilized to capture molecular properties of the tumor microenvironment beyond traditional expression profiling. This innovative method allows for the interrogation of the function of multiple checkpoints and signaling pathways, enabling a deeper understanding of tumor activity and response to therapies. Second, investigations presented here delved into the role of AXL tyrosine kinase in melanoma and its complex interactions in the tumor microenvironment, particularly with tumor- associated macrophages (TAMs). Prior research focused on oncolytic viruses (OV) and ICB, particularly in relationship to the multi-faceted roles of TAMs, have highlighted significant gaps in understanding the intricate interactions within the tumor-immune microenvironment (TiME), ultimately affecting treatment outcomes. Studies presented in this thesis elucidated the function of AXL in multiple melanoma models, providing novel insights into immune responses impacted by AXL function and the potential to exploit these mechanisms to improve immunotherapeutic strategies. These mechanistic studies, utilizing in vivo and in vitro models of multicellular dynamics and multiple AXL inhibition strategies, reveal context-dependent relationships between AXL activity, macrophage functions, and immune recognition of tumors. The synergistic effects of AXL inhibition and anti-PD-1 immunotherapy may offer promising avenues for enhancing tumor control in anti-PD-1-resistant melanoma. Further investigations are needed to enhance predictive accuracy and refine patient stratification strategies for immunotherapy. In parallel, exploring the neoadjuvant setting and leveraging advances in regional therapies offer promising avenues to augment immune responses, control tumor growth, and foster durable therapeutic outcomes. By delving into checkpoint ligand-receptor engagements involving non-tumor immune cells and TAMs, functional assessments of interactive states in tumors stand out as promising tools for enhancing precision immunotherapy and delineating optimal treatment strategies tailored to individual patient profiles. Continued research efforts are vital to unraveling the complexities of melanoma-immune interactions and paving the way for personalized interventions and strategic drug combinations to effectively target immunosuppressive tumor environments and enhance treatment outcomes for patients with melanoma.

Importance: Variably considered as a localized subtype of pustular psoriasis, palmoplantar pustulosis (PPP) is commonly treated with topical steroids, acitretin, and local phototherapy with oral or topical psoralen (PUVA). The utility of acitretin for PPP is limited by adverse effects such as myalgias and an extended risk of teratogenicity in female patients. Isotretinoin is a more tolerable retinoid with a shorter teratogenic window, but to date its effectiveness in PPP has not been reported. Herein we present two patients with PPP who responded well to isotretinoin treatment.

Observations: Two patients with PPP refractory to topical therapies were started on acitretin. Both patients developed adverse effects (including headache, myalgias, and mood alterations) leading to acitretin discontinuation. Isotretinoin monotherapy was started in one patient resulting in significant clearing of palmar plaques and scale, and the addition of isotretinoin to UVA therapy resulted in near-complete clearing of recalcitrant plantar plaques in the second patient.

Conclusions and Relevance: Acitretin represents an important treatment for PPP, but is limited by adverse effects and extended teratogenicity. Our experience supports the utility of isotretinoin as a potential therapeutic alternative, which may be particularly beneficial in patients who are poor candidates for or unable to tolerate acitretin therapy.