Characterization of NK cell phenotypes and their interaction with tertiary lymphoid structures in clear cell renal cell carcinoma (ccRCC)

• Grant number: 25/11140-5
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: October 01, 2025
• End date: May 31, 2026
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Tiago Góss dos Santos
• Grantee: Emmanuel Vinicius Oliveira Araujo
• Supervisor: Tiago da Silva Medina
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
• Institution abroad: University of Southern Denmark (SDU), Denmark
• Associated to the scholarship: 22/00747-8 - Evaluation of the antitumoral activity of CD39+ T cells in patients with clear cell renal cell carcinoma, BP.DR

Abstract

The understanding of the immune infiltrate and its organization within the tumor microenvironment has been transforming cancer management. In this context, tumor-associated tertiary lymphoid structures (TLS) have been linked to improved prognosis in different types of tumors, including clear cell renal cell carcinoma (ccRCC). In principle, TLS are defined as aggregates of B cells surrounded by a mantle of T lymphocytes that facilitate cell-to-cell communication and antigen presentation, thus favoring the initiation and coordination of local adaptive antitumor immune responses. However, the role of natural killer (NK) cells within TLS remains unappreciated. Here, we provide evidence of NK cell localization within tumor-associated TLS. Through single-cell transcriptomics data integration and validation, we have identified for the first time a highly abundance NK cell subpopulation exhibiting a CD56bright NK cell phenotype within mature TLS (mTLS). Notably, CD56bright NK cells were strongly associated with immunomodulatory functions, as they were great producers of cytokines and chemokines in the context of TLS maturation. We also uncovered that NK cells residing outside mTLS exhibited a distinct transcriptional profile, characteristic of cytotoxic NK cells, compared to NK cells from adjacent normal tissue or tumors without mature TLS (mTLS¿), suggesting a TLS-influenced functional reprogramming. Furthermore, we demonstrated that NK cells isolated from mTLS¿ tumors were highly functional compared to their counterparts from mTLS- tumors, suggesting that the formation and maturation of TLS shape the effector functions of NK cells. These results point that NK cells may play a key role on the orchestration of the anti-tumor immune response. To elucidate the cellular components involved in the activation and differentiation of NK cells within TLS and determine whether this imprinting enhances their cytotoxic capacity against tumor cells, approaches including spatial transcriptomics, targeted multiplex immunofluorescence and 3D co-culture assays will be instrumental. Having the opportunity of conducting research at the University of Southern Denmark (SDU), a leading Danish institution where such state-of-the-art methodologies have been implemented, the BEPE fellowship would enable me to uncover cellular interactions and spatial relationships within the TLS, potentially offering key insights for the development of novel therapeutic strategies for ccRCC. (AU)