Tertiary lymphoid structures harbour stem-like tumour-specific T cells

Area of Science:

• Immunology
• Oncology
• T cell biology

Background:

• Tertiary lymphoid structures (TLSs) are linked to better outcomes with immune checkpoint blockade in solid tumors.
• The precise impact of TLSs on the characteristics of tumor-specific T cells is not fully understood.

Purpose of the Study:

• To investigate how TLSs influence the phenotype and function of tumor-specific T cells in treatment-naive renal cell carcinoma (RCC).
• To explore the mechanisms of immune evasion in TLS-containing RCC tumors.

Main Methods:

• Analysis of T cell infiltration and exhaustion markers in TLS-containing versus TLS-negative RCC tumors.
• Specificity screening of T cell receptors (TCRs) reactive to tumor antigens.
• Characterization of T cell clonotypes enriched within TLSs.
• Assessment of macrophage phenotype and localization in TLS-rich tumors.

Main Results:

• TLS-containing RCC tumors showed increased infiltration of exhausted CD8+ T cells but a less pronounced terminal exhaustion program.
• A subset of tumor-specific T cell clonotypes (12%) was enriched in TLSs, exhibiting stem-like progenitor exhaustion phenotypes associated with favorable anti-tumor immunity.
• In a subgroup of tumors, immunosuppressive macrophages were found at the margins of TLS-containing tumors, colocalizing with exhausted T cells.

Conclusions:

• TLSs act as reservoirs for tumor-specific T cells with stem-like progenitor features, potentially beneficial for anti-tumor immunity.
• Immunosuppressive macrophages may represent a mechanism of immune evasion that counteracts T cell-mediated anti-tumor responses in TLS-positive RCC.