Hallmarks of adaptive immunity in a metastatic clear cell renal cell carcinoma (ccRCC) long-term elite survivor

Abstract Clear cell renal cell carcinoma (ccRCC) presents with metastatic disease in nearly one-third of patients, with a 5-year survival of only ∼10%. Although anti-angiogenic therapies and immune checkpoint inhibitors (ICIs) have improved outcomes, therapeutic resistance and immune-related adverse events limit durable responses. Exceptional long-term survivors provide a unique opportunity to uncover mechanisms of sustained anti-tumour immunity and guide therapeutic strategies. Here, we present a spatial and temporal dissection of adaptive immunity in an extraordinary 16-year ccRCC survivor, integrating single-cell sequencing, multiplex immunofluorescence, B and T cell receptor (BCR/TCR) repertoire analysis, and antibody profiling. We reveal persistent and spatially coordinated B and T cell clones over 16 years, indicating long-term immune memory and surveillance throughout tumour evolution. B cell analysis identified pronounced clonal expansions involving intrinsically autoreactive IGHV4-34 B cells undergoing ongoing germinal centre (GC) maturation in tumour-draining lymph nodes (dLNs) and spleen. These clones progressively lost autoreactivity while acquiring tumour-specificity through somatic hypermutation (SHM), consistent with clonal redemption. Redeemed B cells displayed enhanced antigen-presenting functions and localised to tertiary lymphoid structures (TLS), where they interacted with CD8⁺ T cells, as inferred from doublet analysis. In parallel, persistent CD8+ effector T cell clones highlighted the contribution of long-lived lymphocytes to tumour control. Comparison of the primary tumour and pancreatic metastatic with paired tumour-free dLNs showed that TLS mirrored GC functionality, particularly for PD-1+ CD8+ T cells, while TLS maturation was stroma-dependent and impaired at the metastatic site. Finally, tumour-derived BCRs revealed antibody binding to tumour specific “public” antigens without cross-reactivity to normal tissue. Together, these findings establish clonal persistence, TLS engagement, and coordinated B-T cell immune surveillance as hallmarks of durable tumour control, providing a framework for next-generation antibody therapeutics and patient stratification in metastatic ccRCC. What is already known on this topic. Tertiary lymphoid structures within the tumour microenvironment (TME) and clonal expansions of CD8+ T cells are associated with better survival and improved response to immunotherapies in ccRCC. However, identifying markers of prolonged survival is challenging due to the rarity of long-term survivors (LTS), and the predominance of studies focused on T cell immunity, leaving B cell contribution almost unexplored. What this study adds. This study provides an integrated analysis of B and T cell responses in an exceptional 16-year LTS with metastatic ccRCC, revealing key immunologic features of sustained anti-tumour immunity. Beyond T cell dynamics, it highlights the multifaceted role of B cells as antigen presenting cells, antibody producers, and modulators of CD8+ T cell effector functions through direct interactions within TLS. Importantly, it reveals potential tumour-specific antigens driving humoral responses. How this study might affect research, practice or policy. By uncovering mechanisms of sustained tumour control, this work establishes a framework for identifying adaptive immune biomarkers of long-term survival and refining patient stratification in metastatic ccRCC. Multimodal assessment of B cell specificity and spatial interactions between re-educated B cells and CD8+ T cells within TLS introduces a new paradigm for understanding coordinated B and T cell responses. These insights have direct implications for antibody-based drug discovery and development of immunotherapies that harness the B-T cell axis. Competing Interest Statement R.J.M.B.-R. is a co-founder of Alchemab Therapeutics Ltd and consultant for Alchemab Therapeutics Ltd, Roche, Enara Bio, UCB and GSK. The remaining authors declare no competing interests. Footnotes ↵* senior author