The clinical success of immune checkpoint blockade in the treatment of various cancer types provides proof-of-principle that targeting immunosuppression in the tumor microenvironment is an effective therapeutic strategy. Regulatory T cells (Tregs) are a CD4+ T lymphocyte population that may play a dominant role in impairing anti-tumor immune responses. Characterized by their expression of the transcriptional regulator FOXP3, Tregs can inhibit adaptive immune responses through the production of inhibitory cytokines, direct cell killing, competition with other T cell subsets for antigen or other substrates, and suppression of antigen presentation. To recapitulate the strong immunosuppression observed in endogenous tumors, we have used an autochthonous, inducible mouse model of lung adenocarcinoma previously generated in the Jacks lab that is driven by expression of oncogenic KrasG12D and loss of p53 (KP model). Indeed, tumor development in the KP model is accompanied by an expansion of lung-resident Tregs, and previous work in the lab has shown that this population actively restrains anti-tumor T cell responses. In this study, we have transcriptionally profiled lung Tregs in the KP model to identify pathways to preferentially target Tregs in tumor-bearing lungs. We have shown that lung Tregs have a distinct transcriptional phenotype that shares characteristics with that of previously described “effector” Treg populations in a variety of tissue and inflammatory contexts. Furthermore, the KP lung Treg gene signature is associated with survival when applied to the bulk transcriptomes of various tumor types, and is better correlated with patient outcome in lung adenocarcinoma than a number of immune parameters, including mutation burden and expression of CD8A, FOXP3, and GZMA. Together, our data demonstrate that a gene expression signature drawn from cancer-associated Tregs with a distinct, functional phenotype may be useful as a biomarker for clinical outcomes in multiple tumor types.

Citation Format: Amy Li, Arjun Bhutkar, Nikhil S. Joshi, Tyler E. Jacks. Molecular profiling of regulatory T cells in a genetic mouse model of lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A66.