Tertiary lymphoid structures and their association with immune checkpoint inhibitor response and survival outcomes in patients with non-small cell lung cancer.

Abstract

2634 Background: Immune checkpoint inhibitor (ICI)-based therapy is currently the first-line treatment for patients with lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) without actionable mutations. However, the commonly utilized biomarkers, including PD-L1 protein expression and tumor mutation burden, are not sufficiently accurate to predict the treatment response from ICI in this patient population. As tumor microenvironment (TME) and tertiary lymphoid structure (TLS) play a significant role in antitumor immunity, we explore these immunophenotypic factors to determine the potential biomarkers in patients with LUAD or LUSC. Methods: We evaluated all patients with LUAD or LUSC from three publicly available data and two novel retrospective cohorts for transcriptomic-based immune TME subtype classification (immune-hot vs. immune-cold) and TLS signature, along with associated clinical and genomic data. Those with other histological subtypes of non-small cell lung cancer or those who harbored EGFR mutations or ALK rearrangements were excluded from our study. The cellular decomposition within tumor samples was calculated using the deconvolutional Kassandra algorithm. Survival analysis was evaluated using log-rank test and multivariate Cox regression adjusted by PD-L1 status, KEAP1/STK11/KRAS/TP53 mutational status, immune TME subtype, and TLS signature. All statistical analyses were performed using Python. Results: A total of 514 patients were included from five cohorts, with 272 and 505 having genomic and transcriptomic data, respectively. 59% of patients with LUAD or LUSC exhibited an immune-cold phenotype, which correlated with adverse overall survival (OS) and progression-free survival (PFS) than immune-hot phenotype in LUAD. However, the ICI response rates were similar in both groups. Superior PFS and ICI response rates were observed in patients with high TLS signatures (> 88th percentile) in LUAD, even after multivariate adjustments. Immune signatures that were positively associated with ICI response included the infiltration and trafficking of T and NK cells for LUAD and B-cell percentage for LUSC. In contrast, CD8 + T-cell abundance did not correlate with ICI response. The presence of KEAP1 or STK11 mutations also did not affect the response rates but were associated with shorter OS and PFS. Conclusions: Transcriptomic-based immune-hot TME and high TLS signature may serve as novel predictive and prognostic biomarkers in patients with LUAD, while the presence of KEAP1 or STK11 mutations only offered prognostic values. Further prospective studies are warranted to expand to other treatment combinations with PD-(L)1 inhibitors.