75MO - Atlas of tertiary lymphoid structures in solid tumors: Genomic features and prediction of response to immunotherapy

Background

Tertiary Lymphoid Structures (TLS) are pivotal in the tumor microenvironment, associated with improved outcomes and enhanced responses to immune checkpoint inhibitors (ICIs) across various solid tumors. This study investigates the correlation between TLS presence, defined by gene expression signatures, and patient outcomes in cancer treatments involving ICIs, utilizing a comprehensive dataset.

Methods

A retrospective analysis of DNA (592-gene or whole exome) and RNA-seq (whole transcriptome) data was performed on 204,231 patient samples across over 50 cancer types. We assessed gene signatures indicative of B cell infiltration/TLS presence (Messina et al., 2012; Goc et al., 2014; Cabrita et al., 2020; Meylan, et al., 2022), correlating these with clinical outcomes, including overall survival (OS) and time on treatment (TOT) for ICIs such as pembrolizumab, nivolumab, and ipilimumab. Genomic profiles of tumors enriched with TLS-related B cell signatures were further analyzed for predictors of TOT for ICIs.

Results

High TLS scores were observed in NSCLC, head and neck cancers, melanoma, and genital tract malignancies, while lower scores were seen in central nervous system tumors and soft tissue sarcomas. TLS scores were weakly correlated with tumor mutational burden (TMB). However, a strong association was found between high TLS scores and prolonged ICI TOT/improved OS in multiple cancer types, notably in NSCLC (HR 0.86/0.77), bladder cancer (HR 0.78/0.77), breast cancer (HR 0.76/0.63), renal cancer (HR 0.83/0.90), endometrial cancer (HR 0.84/0.79), and soft-tissue sarcomas (HR 0.71/0.75), p<0.0001. Multivariate analyses further indicated a significant association between TLS signature scores and ICI TOT and OS independent of patient age, sex, TMB and microsatellite instability (MSI) status. In NSCLC with high TLS scores, resistance to immunotherapy was enriched in patients with mutations in EGFR, KEAP1, KRAS, or STK11 genes. In MSS colorectal cancer with high TLS scores, resistance was associated with mutations in the APC gene.

Conclusions

This large TLS atlas based on real-world data demonstrate that TLS gene is a robust biomarker for predicting responses to immunotherapy in solid tumors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

CARIS.

Funding

CARIS.

Disclosure

All authors have declared no conflicts of interest.