Abstract LB-498: Density of tertiary lymphoid structures is associated with activated and effector-memory T lymphocyte infiltration in human lung tumor

Abstract

Abstract Introduction: An increasing number of studies have demonstrated a strong correlation between T cell infiltrate and clinical outcome in several types of human solid cancers. Nevertheless, the mechanisms governing T-cell infiltration and activation into tumors remain poorly characterized. In lung cancer, our team has observed the presence of tertiary lymphoid structures called Ti-BALT (Tumor-induced Bronchus-Associated Lymphoid Tissues). These structures present features of an ongoing immune response and their density is associated with long-term survival for lung cancer patients, suggesting their implication in local T cell recruitment and activation. We recently published a specific gene expression signature associated with T cell presence in Ti-BALT, which includes lymphoid chemokines, adhesion molecules, and integrins (De Chaisemartin L, et al. Cancer Research 2011). This chemoattractant gene expression signature strongly suggests an active recruitment of immune cells in these structures. Our aim was to study the influence of these structures on the composition, density and functionality of the immune infiltrate in lung tumors. Methods: The expression of relevant molecules was assessed on fresh tumor-infiltrating lymphocytes by multicolor flow cytometry, on tissue sections by immunohistochemistry and on frozen tumors by Low Density Array analysis. Results: Large-scale flow cytometry analysis revealed an increased infiltration of T and B but not NK cells in tumors with a high density of Ti-BALT as compared to tumors with a low density. A significant increase proportion of activated and effector-memory T cell subsets was observed in Ti-BALT high versus low tumors. Whereas most T cells located in Ti-BALT had a naive and early memory T cell phenotype, as observed in canonical secondary lymphoid organs, T cells located outside Ti-BALT were significantly enriched in effector-memory T cell phenotype. Finally, Ki-67+ proliferating T cells were found in close contact with mature dendritic cells in Ti-BALT, suggesting a local priming of T cells in these structures. Conclusion: Together, these data suggest that Ti-BALT represent a privileged area for T cell recruitment and activation in the primary site of the tumor. This mechanism could lead to the establishment and maintenance of a protective anti-tumor immune response directly in the tumor. These findings give news insights about mechanisms of T cell infiltration and activation in tumor microenvironment, suggesting new strategies to enhance the efficacy of cancer immunotherapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-498. doi:1538-7445.AM2012-LB-498