Evaluation of the Therapeutic Potential of Germinal Center B Cells in Clear Cell Renal Cell Carcinoma Patients

Abstract

Chimeric Antigen Receptor T-cell therapy (CAR-T) stands as a significant breakthrough in the evolving field of immunotherapy. However, due to the lack of well-defined molecular targets in solid tumors, its efficacy has been confined to the treatment of hematological malignancies. The diverse repertoire of B cell receptors (BCR) suggests the presence of a specific B cell subpopulation with increased affinity for tumor antigens, serving as a pivotal tool in constructing chimeric receptors. The tumor antigen recognition from B cells is facilitated in tertiary lymphoid structures (TLS), mostly located in tumor regions. Recent investigations underscore the clinical advantages linked to the presence of TLS, particularly in Clear Cell Renal Carcinoma (ccCRC), since these structures facilitate cell-to-cell interaction, thereby fostering robust immune responses against tumor antigens. Notably, the clinical benefits of TLS depend on their maturation stage, marked by the formation of a germinal center (GC). Within the GC, B cells undergo a series of events, including differentiation and antibody affinity maturation that lead to the generation of antibody-secreting plasma cells. Recent investigations suggest that tumor-specific antibodies secreted in the intratumoral area indeed originate from the differentiation of GC B cells within TLS and are associated with the apoptosis of tumor cells. Hence, this study aims to comprehensively analyze the BCR repertoire of GC B cells, specifically those exhibiting the CD19+CD38+FAShiIgD- phenotype. The investigation will encompass an analysis of the B cell production of high-affinity IgG, along with their capacity for binding to primary ccCRC cells. Additionally, the study will delve into the composition of high-affinity IgG, ultimately paving the way for the construction of a personalized chimeric receptor to empower the generation of CAR-T cells with potent activity against ccCRC.