Tertiary lymphoid structures are reservoirs of stem-like tumor-specific T cells in renal cell carcinoma

Journal article

Tertiary lymphoid structures (TLS) are associated with improved response to immune checkpoint blockade across solid tumors, but how they impact the phenotypic properties of tumor-specific T cells remains unknown. Across 24 treatment-naïve renal cell carcinoma (RCC) tumors, TLS-containing tumors were more heavily infiltrated by exhausted CD⁸⁺ T cells with a reduced terminal exhaustion transcriptional program compared to TLS^- tumors. Specificity screening of 554 T cell clonotypes expanded within the microenvironment of 6 RCC tumors revealed 82 TCRs reactive against tumor cells and/or RCC antigens. A subset of tumor-specific T cell clonotypes (12%) was enriched within TLS, and these expressed an increased program of stem-like progenitor exhaustion, associated with favorable anti-tumor immunity. However, in 60 independent RCC tumors, macrophages within tumor margins of TLS-containing tumors bore an inferred immunosuppressive phenotype, and were colocalized with exhausted putative tumor reactive T cells in a subgroup that was further analyzed, thus supporting this mode of immune evasion as a counterbalance to T cell immune pressure. Our data reveal TLS as reservoirs of tumor-specific T cells with stem-like progenitor features that could be leveraged by T cell immunotherapies.

Authors: Afeyan, AB; Nagler, A; Tu, CR; De Oliveira, GR; Simsek, B

• Publication status: Accepted
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature
• Acceptance date: 2026-05-01
• EISSN: 1476-4687
• ISSN: 0028-0836
• Language: English