Abstract B15: Increased presence of T follicular helper cells in lung adenocarcinoma is associated with mutational load

Abstract

Tertiary lymphoid organs are ectopic lymphoid formations found in inflamed tissues such as tumors, and their presence has been associated with improved patient outcome. T follicular helper cells (Tfh) reside in the germinal centre of tertiary lymphoid organs, and are required for the maturation of B cells and subsequent antibody response. Whereas the prognostic value of Tfh has been described in breast and colon tumors, they remain uncharacterized in lung tumors. We hypothesize that Tfh cells reside in lung adenocarcinomas and are associated with an increased immune response due to neoantigen exposure. Gene expression profiles were obtained from 83 paired lung adenocarcinomas and nonmalignant lung tissues from the BC Cancer Agency, and 571 unpaired samples from The Cancer Genome Atlas. Relative proportions of 22 immune cell subsets were inferred from gene expression data using CIBERSORT, a deconvolution algorithm. Identification of tertiary lymphoid organs was achieved through multicolor immunohistochemistry (IHC) staining for T- and B-cell lineage markers (CD3 and CD79a) using whole tissue sections. Proportions of Tfh cells were correlated with tumor mutation load defined as non-silent mutations per megabase (Mann Whitney U test) and patient outcome (Cox proportional hazard model). The proportion of Tfh cells was significantly increased in tumor tissue compared to nonmalignant lung in both cohorts. We also observed concomitant upregulation of Tfh markers PD1 and CXCR5 . Multicolor IHC validated the presence of tertiary lymphoid organs in 19 out of 20 cases assessed. Intriguingly, the increase in the proportion of Tfh cells revealed by CIBERSORT was observed across all disease stages and was validated in an additional cohort of Stage I lung adenocarcinomas. The relative proportion of Tfh cells did, however, increase with increasing tumor mutation burden, suggesting their involvement in an active immune response against tumor neoantigens. Tfh recruitment appears to be an early event in lung tumor progression and a function of neoantigen exposure, suggesting involvement in an active antitumor response rather than a passive result of chronic inflammation. Further investigation into Tfh in lung adenocarcinomas may lead to prognostic applications. Citation Format: Katey S.S. Enfield, Kevin W. Ng, Erin A. Marshall, Spencer D. Martin, Wan L. Lam. Increased presence of T follicular helper cells in lung adenocarcinoma is associated with mutational load [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B15.