Immune Architecture in Stage III and IV Melanoma Identifies Distinct Patient Subgroups

Joel Eliason ¹ Santhoshi Krishnan ¹ Yasunari Fukuda ² Matias Bustos ³ Dan Winkowski ⁴ Sun-Nam Cho ⁵ Akshay Basi ⁵ Regan Baird ⁴ Elizabeth A Grimm ⁵ Michael A Davies ⁵ Dave Hoon ³ Arvind Rao ¹ Jared Burks ⁵ Suhendan Ekmekcioglu ^5*

• ¹ University of Michigan, Ann Arbor, Michigan, United States
• ² Kindai University Nara Hospital, Oda-machi, Nara, Japan
• ³ Saint John's Health Center, Santa Monica, California, United States
• ⁴ Visiopharm A/S, Hørsholm, Denmark
• ⁵ University of Texas MD Anderson Cancer Center, Houston, United States

The clinical use of immune checkpoint inhibitors (ICIs) has significantly transformed treatment strategies for patients with various cancers, including melanoma, in both advanced and adjuvant settings. Given the aggressive nature of advanced melanomas, there is an urgent need to optimize ICI-based treatment approaches. Here, we aim to characterize the immune architecture of the tumor immune microenvironment (TIME) and its role in the progression of Stage III and IV melanomas. We hypothesize that innate inflammatory enzymes and their mediators in the melanoma TIME contribute to "immune exclusion" by altering tissue structure, thereby preventing an "immune-inflamed" state that would otherwise enhance tumor responsiveness to therapy. To address the complexity of the TIME in these patients, we first visualized this highly intricate cellular environment and analyzed it in its intact form across multiple protein biomarkers. Our approach integrates two complementary platforms: one for assessing cellular, functional, and structural marker signatures and another for profiling inflammation signatures. This strategy enables a comprehensive analysis of immune architecture and its correlation with clinical outcomes, providing novel insights into immune dynamics in melanoma progression.