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RP3

Thomas Worzfeld: Plexin-mediated regulation of anti-tumor CD8⁺ T cell activity in the tumor microenvironment

AIM: Accumulating evidence suggests that T cell exclusion and exhaustion may be driven by secreted factors in the TME. However, the identities of T cell-suppressive ligand-receptor systems operating in the TME are only partly known. Based on our preliminary data, we hypothesize that semaphorin-plexin signaling suppresses CD8⁺ T cell activity in the TME, thereby driving T cell exclusion and impeding anti-tumor activity of CD8⁺ T cells to promote tumor  growth and therapy resistance. The objectives of this project are to characterize the functional role of semaphorin-plexin signaling in CD8⁺ T cells of the TME, to uncover the involved cellular and molecular mechanisms with a particular focus on the TME secretome, and to evaluate the potential of this signaling pathway as a pharmacological target for cancer therapy.

STATE of the ART: CD8⁺ T cells are powerful effectors in the anticancer immune response and play a pivotal role in cancer immunotherapies. However, the  TME is frequently characterized by relatively low numbers of cytotoxic CD8⁺ T cells, which often display states of low activation. Therefore, the blockade of T cell-suppressive secreted factors and their receptors in the TME, in order to leverage the anti-cancer activity of CD8⁺ T cells, could represent a promising therapeutic strategy in cancer. This approach requires the identification and characterization of T cell-suppressive ligand-receptor systems operating in the  TME, which to date remain poorly defined.
Work of the last two decades has revealed the biological significance of the semaphorin-plexin-system in various biological contexts including the tumor microenvironment. These studies have mostly focused on the function of plexins in cancer cells, where they might regulate proliferation, migration, and invasion. The significance of semaphorins and plexins in T cells and their impact on the TME is unclear.