Sex-Specific Mechanisms of Immune Evasion in Cutaneous Melanoma

Elise Di Lena

Kazuaki Takabe, MD, PhD, FACS, FSSO

Resident/Fellow Award

Roswell Park Cancer Institute

In Memory of Richard Draeger

Melanoma remains a critical health challenge where a significant disparity exists: men experience worse survival rates than women. Even when diagnosed at the same stage and treated with identical immunotherapies, male patients are less likely to respond. This suggests that current “one-size-fits-all” treatments fail to account for fundamental biological differences in the male immune system. A central paradox is that male tumors often carry more mutations. Biologically, high mutation rates usually make cancer easier for the immune system to detect because the cells look more “foreign.” Yet, the male immune response is frequently suppressed. My research proposes that this is due to “alternative brakes”—distinct molecular checkpoints (like VISTA or LAG3) that male tumors activate to shut down immune cells. Because standard therapies (like anti-PD1) do not target these specific male-biased brakes, the immune system remains paralyzed. To solve this, I will use advanced computational analysis of Single-Cell RNA Sequencing data. Historically, cancer research treated tumors like a “smoothie,” blending all cells together to get an average measurement that obscures critical details. My project treats the tumor like a “fruit salad,” analyzing thousands of individual cells to uncover the rare, specific defects in the male immune environment that are invisible to standard bulk sequencing. This high-resolution approach allows me to: 1. Identify the specific immune cells in men that are “exhausted” or inactive. 2. Map the chemical signals the tumor uses to suppress them. 3. Develop a “Male Resistance Score” to predict which patients are at high risk of treatment failure. By understanding these sex-specific mechanisms, we can move toward true personalized medicine. This research could eventually save patients from wasting months on ineffective therapy, guiding them instead toward drug combinations tailored to their specific biological sex.