220P - Heterogeneity in tertiary lymphoid structures predicts distinct prognosis and immune microenvironment characterizations of clear cell renal cell carcinoma

Background

Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that develop postnatally in non-lymphoid tissues and are associated with pathological conditions. However, the precise relationship between localization and maturation of TLS and the clinical outcome of their presence in clear cell renal carcinoma (ccRCC) is yet to be elucidated.

Methods

Immunohistochemistry and multispectral fluorescent were used to evaluate the TLS heterogeneity along with TME cell-infiltrating characterizations. A thorough investigation of the prognostic implications of the TLS heterogeneity was conducted. Associations between TLS heterogeneity and immunologic activity were assessed by quantifying the immune cell infiltration.

Results

Infiltrated TLS were identified in 34.2% of the ccRCC samples (N=395). These TLS were found to be tumor-proximal, tumor-distal, or both in 37.8%, 74.1%, and 11.9% of the TLS-positive cases, respectively. A higher proportion of early TLS was found in tumor-distal TLS (P=0.016), while tumor-proximal TLS primarily comprised secondary follicle-like structures (P=0.004). Kaplan–Meier analyses revealed a significant correlation between the presence of tumor-proximal TLS and improved PFS (P<0.001) and OS (P=0.002). Conversely, the presence of tumor-distal TLS was associated with poor PFS (P=0.02) and OS (P=0.021). Notably, the presence of mature TLS was significantly associated with better clinical outcomes in patients with ccRCC. Novel nomograms incorporating the presence of tumor-proximal TLS demonstrated remarkable predictability for the 8-year outcomes of resected ccRCC. Additionally, ccRCC samples with tumor-distal TLS enriched with primary follicle-like TLS exhibited higher PD-L1⁺ tumor-associated macrophages levels and regulatory T cells infiltration in the tumor-distal region, indicative of a suppressive TME.

Conclusions

This study for the first time elucidates the impact of TLS localization and maturation heterogeneities on the divergent clinical outcomes of ccRCC. The findings reveal that most TLS in ccRCC are located in the tumor-distal area and are associated with immature, immunosuppressive characterizations.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

National Natural Science Foundation of China.

Disclosure

All authors have declared no conflicts of interest.