Abstract PR06: Investigating ectopic lymphoid aggregates in a genetically engineered mouse model of lung adenocarcinoma
Authors: Kelli Connolly, Mursal Nader, Nikhil Joshi
Journal: Clinical Cancer Research (2018)

Abstract Ectopic lymphoid aggregates (LA) located in the vicinity of solid tumors have been identified in human patients with many types of cancers and have been largely associated with improved outcomes. In particular, LA in patients with non-small cell lung cancer have been associated with longer overall survival, regardless of the presence of intratumoral CD8 T cells, a commonly used prognostic marker. Tumor-associated LA are organized similarly to lymph nodes with distinctive T-cell zones, B-cell zones, and high endothelial venules (HEV), suggesting a role of LA in the regulation of an antitumor immune response. Therefore, therapeutics targeting these LA have potential to strengthen the antitumor immune response and consequently improve patient outcome. Nevertheless, there is an absence of preclinical models that mirror this clinically relevant phenomenon, and thus their formation and precise function(s) remains poorly understood. Using a genetically engineered mouse model (GEMM) of lung adenocarcinoma in immunocompetent KP-T mice (KrasLox-STOP-Lox-G12D;p53flox/flox;Rosa26Lox-STOP-Lox-tdTomato), we have observed that tumor-associated LA develop and serve as critical sites for the regulation of antitumor immune responses. In this model, autochthonous tumors develop about 20 weeks after intratracheal infection with Cre recombinase-encoding lentivirus (Cre LV), and progress in a similar manner to human disease. The expression of an antigenic construct containing three well-characterized T-cell antigens fused to luciferase (LucOS) was introduced into developing tumors via LV (LucOS/Cre LV). Interestingly, tumors expressing these antigens are physically associated with LA, whereas tumors that do not express these antigens are not. We are therefore uniquely positioned to investigate the role of tumor antigens, as well as the subsequent antitumor immune response, in the development of tumor-associated ectopic LA. We hypothesize that tumor antigen-specific, “pioneering” T cells trigger the recruitment of other immune cell types and ultimately lead to the formation of tumor-associated LA and the development of an antitumor immune response. Future studies will investigate the role of tumor-specific CD8 T cells in the formation of LA, using various GEMM and LV infections to manipulate and “turn off” the expression of T cell antigens by tumor cells. To advance our understanding of cancer outcomes and select more effective, individualized treatments for patients, we believe that it is crucial to directly interrogate how and when LA develop. Ultimately, our findings will identify cellular and molecular targets essential to the formation and maintenance of LA, thus providing candidates for therapeutic modulation of these clinically relevant tumor-associated immune structures. This abstract is also being presented as Poster B14. Citation Format: Kelli Connolly, Mursal Nader, Nikhil Joshi. Investigating ectopic lymphoid aggregates in a genetically engineered mouse model of lung adenocarcinoma [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 PR06.