Novel synaptic filopodium-like protrusions (SFPs) protect tumor cells against cytotoxic lymphocyte-mediated killing

Cytotoxic lymphocytes (CLs) are key anti-tumor immune effector cells. They physically interact with prospective target cells through a highly specialized cell-to-cell interface termed immunological synapse. This interface is indispensable for recognition of cancer cells and activation of CL cytolytic functions. Recently, we established that cancer cell intrinsic resistance to CL-mediated killing correlates with fast and massive accumulation of actin filaments to the immunological synapse or "actin response". Remarkably, inhibition of the actin response is sufficient to restore cancer cell susceptibility to CL-mediated killing in vitro and a potent anti-tumor immune response in vivo. Conversely, enhancing the capacity of cancercells to mount an actin response translates into tumor immune evasion, both in vitro and in vivo. Super resolution microscopy and ultrastructure investigations revealed that the actin response consists of many actin-rich filopodial protrusions projecting into the synaptic cleft and that are heavily decorated with the immune checkpoint molecule PD-L1. Inthe SYNAPODIA project, we aim at characterizing the molecular identity and functions of these newly discovered synaptic protrusions. Based on our preliminary data, we propose that they critically contribute to immune checkpoint activation by driving PD-L1 polarization toward conjugated CLs. In addition, we aim at understanding how this synaptic evasion mechanism alters the tumor immune landscape in vivo. Finally, we will evaluate the therapeutic potential of targeting the actin response and synaptic filopodia in combination with immune checkpoint blockade therapy.