482 Tertiary lymphoid structures as markers of anti-tumor immunity with independent prognostic value in the PORTEC-3 trial of high-risk endometrial cancer

Abstract

<h3>Introduction/Background*</h3> Tertiary lymphoid structures (TLS) are ectopic lymphoid tissues that form in and around cancers. TLS consist of a germinal centre (GC) with proliferating B-cells and follicular dendritic cells (FDCs), as well as a peripheral T-cell zone. Local and systemic B- and T-cell responses are thought to be initiated and maintained at the TLS. Here, we analysed whether TLS were associated with anti-tumour immunity and a reduced risk of recurrence in endometrial cancer (EC). <h3>Methodology</h3> TLS were quantified by an expert pathologist (TB) on H&amp;E-stained tumour slides of the cancer genome atlas uterine cancer cohort (TCGA UCEC), and by immuno-histochemistry (IHC) on tumour slides from the PORTEC-3 trial biobank. Time to recurrence analysis were performed according to Kaplan-Meier’s method, using log-rank tests and Cox’ proportional hazards models, including prespecified multivariable analysis with clinicopathological and molecular risk factors. <h3>Result(s)*</h3> Differential gene expression analysis of TLS-positive and TLS-negative cases from TCGA UCEC identified, among others, L1-cell adhesion molecule (L1CAM) (figure 1A). IHC of PORTEC-3 cases revealed expression of L1CAM in TLS GCs, where it co-localised with CD21 on FDCs. TLS were observed in the myometrial wall distal and proximal to the tumour (figure 1B). Tumour tissues of 377 PORTEC-3 participants could be included for analysis of L1CAM-defined TLS. L1CAM-defined TLS were identified independent of L1CAM expression in tumour cells and across all molecular subgroups, though enriched in mismatch repair deficient (MMRd) and polymerase-epsilon mutant (<i>POLE</i>mut) EC (figure 2). TLS were significantly more frequent in MMRd EC with secondary <i>TP53</i> mutations (p=0.008). Intra-tumoural CD8⁺-cell densities were significantly higher in TLS-positive cases. Five-year risk of recurrence was 7.2% (95%CI 0.9-13.1) in EC patients with TLS (n=70), and 27.8% (95%CI 22.6-32.7, p-value &lt;0.0001) in EC patients without TLS (n=307). This favourable prognostic impact was independent of clinicopathological and molecular factors (adjusted HR 0.32 95%CI 0.14-0.74, p=0.0077). <h3>Conclusion*</h3> L1CAM identifies tertiary lymphoid structures with germinal centres. Our data suggest a pivotal role of TLS in the risk of recurrence of EC. L1CAM IHC is simple, available across many study cohorts and could be readily implemented as biomarker of TLS in future trials and clinical care.