Actin remodeling in autophagy-mediated tumor immune escape,mechanistic aspects

Project Details

Description

Natural killer (NK) cells and CD8+ T lymphocytes (CTLs) are cytotoxiclymphocytes with potent activity in eliminating tumor cells. They both directlykill transformed cells and have accordingly a great potential for cancerimmunotherapy. However, the resistance mechanisms mounted by cancercells and immunosuppressive tumor microenvironments remain majorhurdles. Although their activation is regulated by different molecularinteractions with tumor cells, NK cells and CTLs kill their targets usingcommon mechanisms. One potent killing modality involves the formation ofa specific contact interface with the target cell (the immunological synapse)and directed secretion of lytic granules containing cytotoxic mediators, suchas granzyme B. We recently uncovered a pivotal role for the actincytoskeleton in mediating tumor cell resistance to NK cell-mediated lysis.Our findings show that, upon NK cell attack, a massive accumulation ofactin near the synaptic region rapidly takes place in resistant target cells.This so-called "actin response" protects NK cell-conjugated target cells fromapoptosis by decreasing intracellular levels of granzyme B. Our unpublisheddata support that the actin response also provides resistance against tumor-specific CTLs and considerably facilitates tumor growth inimmunocompetent mice. The ACTIPHAGY project aims at characterizingthe mechanism by which the actin response prevents granzyme Baccumulation in target tumor cells and subsequent cell lysis. Based on asolid set of preliminary data we propose that the actin response drivesautophagosome recruitment toward the synaptic region, leading to a localincrease in autophagic flux, accelerated degradation of cytotoxic molecules,and target cell survival
AcronymACTIPHAGY
StatusFinished
Effective start/end date1/12/1930/11/23

Funding

  • FNRS - Fonds National de la Recherche Scientifique: €109,239.00
  • FNRS - Fonds National de la Recherche Scientifique: €93,239.00

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