Significance of tumor reactivity in draining lymph nodes

Authors

• CC Worthy
• J Gatete
• JS Hurston
• BR Schenk
• CW Dubose
• LS Mabundo
• R Jagannathan
• AE Sumner

Abstract

CD8+ T cell responses play a pivotal role in promoting immune recognition against tumors, and the abundance of T cells existing in a stem-like phenotypic state have been associated with increased response to therapy. In scenarios characterized by persistent exposure to antigens, such as cancer and chronic infections, CD8+ T cells with specificity towards these antigens may undergo exhaustion or dysfunction that can manifest through increased expression of inhibitory receptors. Extensive transcriptomic profiling of Tumor Infiltrating Lymphocytes (TIL) across metastatic tumors has demonstrated that anti-tumor T cells tend to exist in an exhausted or dysfunctional state, allowing for successful TCR prediction based on a common exhaustion gene signature. Recent investigations in murine models have revealed the significance of T cells located in peripheral regions, specifically secondary lymphoid organs such as tumor-draining lymph nodes. However, the anti-tumor properties and phenotypic states of T cells within DLNs remains to be fully understood. Fresh Tumor Digest (FTD ), Draining Lymph Node (DLN), and/or PBL sample were obtained from patients undergoing oncologic resections. Single cell transcriptomic analysis was performed for FTD and DLN samples, and TCRs within likely reactive clusters were ordered for functional screening based on neoTCR signature. TCR encoded DNA plasmids were retrovirally transduced into donor PBL using a gp100 cell line, allowing for functional screening of TCRs against neoantigen candidates and patient derived organoid by ELISpot and Flow Cytometry. Reactive TCR clones were then back projected onto single cell transcriptomic data to determine phenotypic states allowing for comparison between sites.

Scientific Focus Area: Immunology

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