The shift to targeted, chemotherapy-free agents for the treatment of chronic lymphocytic leukemia (CLL) has pushed median overall survival beyond seven years, and as a result the leading cause of death in low- and intermediate-risk patients is no longer progressive disease but CLL-associated complications, among them second primary malignancies (SPMs). This risk persists in the era of targeted therapy, with younger and previously treated patients at greatest risk of both solid and hematological second cancers. Yet the role of CLL infiltration and its impact on the tumor microenvironment (TME) in the development of SPMs remains unexplored: while tumor-infiltrating T cells and, more recently, B-lineage cells are recognized as active shapers of antitumor immunity, how leukemic CLL cells interact with the microenvironment of a coexisting second cancer is unknown. To address this, we apply highly multiplexed CODEX imaging (54 protein markers) to tissue microarrays spanning a spectrum of CLL-associated SPMs, mapping the spatial relationships between infiltrating CLL cells and the surrounding tumor niche alongside immune and stromal composition, immune-checkpoint expression, and T-cell exhaustion states. Building on this, we aim to extend toward single-cell spatial profiling to resolve these interactions at finer resolution, comparing immune architecture across cancer types and against control tissue to illuminate the leukemia–tumor interactions that drive CLL-associated SPMs and identify spatial biomarkers of compromised antitumor immunity.

https://www.al-sawaf-lab.com/