Fate mapping LAG3⁺ exhausted CD8⁺ T cells.  

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Presentation Time: 10:15 AM - 10:30 AM
Abstract ID: 5289 - B

Presenting Author:
Vaishali Aggarwal , Post Doctoral Associate at Univ. of Pittsburgh Sch. of Med., UPMC Hillman Cancer Ctr.

Abstract:

T cell exhaustion, a state of T cell dysfunctionality is well defined in chronic viral infections, however, not completely understood in tumor setting. The exhausted T cells (T_EX) express high levels of LAG3, an inhibitory receptor regulating T cell exhaustion. We hypothesize defining lineage heterogeneity and plasticity of LAG3⁺ T cells, would be insightful in determining fate and functionality of these cells. We generated a novel lineage tracing Lag3^iCreERT2 Rosa26^LSL-tdTomato mouse strain facilitating temporal assessment of LAG3⁺ cells using tamoxifen induced pulse/chase scheme. This enables fate-mapping of ‘bona fide’ tumor-reactive LAG3⁺ cells and understanding their transcriptional and epigenetic profiles. We identified two distinct LAG3^- tdT⁺ and LAG3⁺ tdT⁺ exhausted T cell populations characterized with tdT⁺ expression. These two distinct tdT⁺ subsets are transcriptionally, and epigenetically distinct. The LAG3^- tdT⁺ cells are derived from cleavage of surfaceLAG3 and are ‘stem-like’ exhausted CD8+ T cells with intermediate PD-1 expression. These ‘stem-like’ exhausted CD8+ T cells persist in vivo, have differentiation plasticity and contribute to peripheral tumor-specific memory. The other subset, LAG3⁺ tdT⁺ T cells are ‘terminally exhausted’, restricted to tumor microenvironment and express high levels of PD-1, TIM-3 and TIGIT. Overall, this model provides a unique advantage of characterizing LAG3^- tdT⁺ ‘stem-like’ exhausted CD8+ T cells.