Intratumoral tertiary lymphoid structures are associated with disease control and progression-free survival in patients with hepatocellular carcinoma receiving immune checkpoint inhibitors

To assess whether intratumoral tertiary lymphoid structures (TLSs) are associated with outcomes in hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs). This retrospective single-centre study included 49 patients with retained HCC resection specimens. The primary cohort comprised 45 patients with pre-ICI specimens; four post-ICI specimens were excluded. Outcomes were first-assessment disease control by modified Response Evaluation Criteria in Solid Tumours (mRECIST), progression-free survival (PFS) and exploratory overall survival. Transcriptomic analysis included nine pre-ICI tumours (six TLS-positive, three TLS-negative), with the ten-sample comparison retained for sensitivity analysis. There were 37 PFS events and eight deaths. Disease control occurred in 20/21 (95.2%) patients with T-score > 0 versus 10/24 (41.7%) with T-score = 0 ( P < 0.001). T-score > 0 was associated with longer PFS after adjustment for intrahepatic metastasis and ICI-plus-targeted treatment (hazard ratio [HR] 0.290, 95% confidence interval [CI] 0.131–0.642; P = 0.002). The association persisted after excluding eight patients with pre-specimen anticancer treatment (HR 0.232, 95% CI 0.086–0.623; P = 0.004) and adjusting for specimen-to-ICI interval (HR 0.297, 95% CI 0.129–0.681; P = 0.004). T-score interobserver agreement was high (quadratic-weighted κ = 0.974). Transcriptomic analysis identified 129 strict differentially expressed genes. B-cell proliferation was enriched (normalised enrichment score 2.09; false-discovery-rate q = 0.015); other immune themes were exploratory or non-significant after correction. Intratumoral TLSs in archival pre-ICI HCC specimens were associated with disease control and PFS. These retrospective findings are associative rather than predictive and require prospective validation. Not applicable.