PhD Candidate University of Vermont Burlington, Vermont, United States
Disclosure(s):
Katherine Horrigan: No financial relationships to disclose
Introduction/Rationale: gd T cells have been shown to both promote tumor growth/metastasis and to efficiently kill tumor cells. These contrasting roles have been attributed to their different functional subsets, with gdT1 cells being associated with anti-tumor immunity, while gdT17 cells are associated with tumor growth and metastasis. However, the factors that regulate the activation and expansion of these functional subsets, as well as the mechanisms through which they regulate tumor growth are still unclear.
Methods: To investigate these questions, we developed a novel inducible model of Scgb1a1-linked Kras-driven lung adenocarcinoma with or without an Stk11 co-mutation and used multi-color flow cytometry to characterize the tumor-immune microenvironment and single-cell RNAseq to examine both the gd T cells and the tumor lung epithelium.
Results: Upon tumor induction KrasG12D/Stk11fl (KS) mice exhibited significantly higher tumor burden and faster disease progression than KrasG12D (K) mice. The more rapid disease progression in these mice was associated with a significant increase in Vg4 and Vg6 gdT17 cells, but not Vg1 gdT1 cells. scCITEseq revealed significant changes in the transcriptional diversity of the KS lung gdT17 cells that was associated with an expansion of an Areg+ Vg6 gdT17 subset. There was no significant difference, however, in gd T cell proliferation. Investigation of the Scgb1a1+ lung epithelium revealed that KS tumors upregulate the expression of numerous immune-relevant chemokines and cytokines, including Cxcl16. When cultured in vitro, tumor cells but not healthy epithelial cells from KS mouse lungs produced significant levels of CXCL16. Finally, we demonstrated that lung gdT17, but not gdT1 cells, express the CXCL16 receptor CXCR6.
Conclusion: Taken together, these data show that tumor-intrinsic Stk11 loss in lung adenocarcinoma is associated with an expansion of lung gdT17 cells and supports a model in which these pro-tumor cells are recruited to the KS mouse lung via a CXCL16-CXCR6 axis.
