TLSs harbor stem-like tumor-specific T cells in RCC
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A study of 24 treatment-naive renal cell carcinoma (RCC) tumors found that tertiary lymphoid structures (TLSs) are enriched with stem-like progenitor exhausted CD8+ T cells. These cells expressed a reduced terminal exhaustion program compared to TLS-negative tumors. The findings suggest TLSs serve as reservoirs for tumor-specific T cells that could be targeted by immunotherapies.
T Cell Exhaustion Profiles
Across 24 treatment-naive RCC tumors, TLS-containing tumors showed heavier infiltration by exhausted CD8+ T cells with a reduced terminal exhaustion transcriptional program compared to TLS-negative tumors. Specificity screening of 554 T cell clonotypes from 6 RCC tumors identified 82 TCRs reactive against tumor cells or RCC antigens. A subset of tumor-specific T cell clonotypes (12%) was enriched within TLSs and expressed an increased stem-like progenitor exhaustion program.
Immune Evasion Counterbalance
In 60 independent RCC tumors, macrophages within tumor margins of TLS-containing tumors exhibited an inferred immunosuppressive phenotype. These macrophages colocalized with exhausted putative tumor-reactive T cells in a subgroup analyzed further. This supports a model where immune evasion counterbalances T cell immune pressure within TLS-positive tumors.
What's Next
Future studies may explore whether TLS-derived stem-like T cells can be leveraged for T cell immunotherapies. It remains unclear how the immunosuppressive macrophage phenotype can be overcome to enhance anti-tumor immunity.
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TLSs harbor stem-like tumor-specific T cells in RCC
