Elucidating T Cell Ferroptosis in Renal Medullary Carcinoma: 3D Genome Architecture Rewiring and Therapeutic Alleviation

Project Summary The three-dimensional (3D) chromatin architecture in mammals represents a remarkable yet not fully understood biological process. The high-throughput chromosome conformation capture (Hi-C) technique, known as Hi-C, is instrumental in identifying diverse chromatin structures. Despite this, the ways in which the 3D chromatin

architectures in T cells are influenced by the tumor immune microenvironment, and how this impacts cancer outcomes, remain largely unexplored. Renal medullary carcinoma (RMC) stands out as a particularly aggressive cancer that predominantly affects young individuals of African descent, especially those with sickle cell disease

(SCD). Treatment options for RMC are currently limited. The most promising among them are immune checkpoint blockades (ICIs). However, to truly harness the potential of ICI-based therapies, there's an urgent need for a deeper understanding of the RMC immune microenvironment and the underlying mechanisms of

RMC. The 3D chromatin architecture in cells related to RMC remains a relatively uncharted territory. Guided by the expertise of cancer biologist Dr. Liuqing Yang, epigeneticist Dr. Wenbo Li, and Dr. Pavlos Msaouel, a clinician specializing in rare renal carcinomas, our team has harnessed the power of Hi-C. We aimed

to delineate the distinct chromatin structures in CD8+ T cells from SCD patients in contrast to those from healthy individuals and to understand the ramifications of these changes on the development and prognosis of RMC. Intriguingly, our preliminary findings highlight significant modifications in the 3D genomic structure of CD8+ T

cells derived from SCD donors. A notable observation is the diminished chromatin loop stemming from the SLC7A11 locus in the SCD condition. This locus plays a pivotal role in ferroptosis, a specialized form of programmed cell death involving iron. Building on these insights, we postulate that ferroptosis in SCD-induced

CD8+ T cells contributes to the immune resistance observed in RMC, with altered chromatin structures being central to this process. Our project is anchored in three specific objectives: 1) Establish the connection between altered chromatin architecture and the molecular pathway linking SCD and RMC tumorigenesis; 2) Delve into

the 3D genomic mechanisms driving ferroptosis in CD8+ T cells in SCD; 3) Assess the significance of both ferroptosis and the altered genomic architecture in CD8+ T cells on the overall disease landscape. Our team envisions that within a decade, ICI and CAR T-cell therapy will emerge as frontline treatments

for RMC, enhancing cure rates and addressing the current limitations of standard care. By delving into the role of altered 3D chromatin structures in RMC's molecular mechanisms, we hope to equip the scientific community with insights crucial for devising strategies that safely and effectively sensitize RMC to ICI and CAR T-cell

therapies. The data generated from our investigations will lay the groundwork for early-phase clinical studies led by Dr. Pavlos Msaouel. These studies will be pivotal in addressing questions about the next generation of ICI and T-cell therapies tailored for RMC.