1051P - Impact of TLS status on outcomes in patients with high TMB or MSI-high status treated with immune checkpoint inhibitors

Background

Tertiary Lymphoid Structures (TLS) are critical components of the tumor microenvironment and may influence the efficacy of immune checkpoint inhibitors (ICIs). High tumor mutational burden (TMB) and microsatellite instability-high (MSI-High) are now established biomarkers approved to guide treatment with ICIs such as pembrolizumab. This study explores the impact of TLS status on the outcomes of patients with these biomarker-positive profiles undergoing pembrolizumab treatment.

Methods

Retrospectively reviewed DNA (592-gene or whole exome) and RNA-seq (whole transcriptome) data from real-world patient tumor samples with high TMB (>10 mut/Mb) or MSI-High status (N=8792), representing >40 tumor types. PD-L1 expression was assessed by IHC (22c3, 28-8, SP142 tumor cell only, or SP142 immune cell only). TLS signature analysis included specific gene sets indicative of B cell infiltration/TLS presence (Messina et al., 2012; Goc et al., 2014; Cabrita et al., 2020; Meylan et al., 2022), with a specific focus on the highest quartile (Q4) of expression. Survival outcomes and duration of pembrolizumab treatment were compared across patients stratified by high (Q4) versus low (Q1-Q3) TLS gene signature scores.

Results

Patients with high TLS expression (Q4) demonstrated significantly improved survival outcomes and prolonged treatment duration compared to those with lower TLS levels (Q1, Q2, and Q3) across both TMB-high (HR 0.80, 0.85, and 0.92, respectively) and MSI-High groups (HR 0.81, 0.90, and 1.0, respectively), p<0,0001. Multivariate analysis, adjusting for gender, age, tumor type, and PD-L1 expression status confirmed the independent predictive value of high TLS status for better clinical outcomes in this patient cohort.

Conclusions

High TLS gene expression signatures, particularly in the highest quartile, are associated with favorable outcomes in patients with high TMB or MSI-High status treated with pembrolizumab. These findings suggest that TLS status could serve as a potent biomarker to stratify patients more likely to benefit from ICI therapy, advocating for its integration into routine clinical assessments prior to ICI treatment in these specific group of patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Caris.

Funding

Caris.

Disclosure

All authors have declared no conflicts of interest.