Cytotoxic T lymphocytes (CTL) and natural killer cells (NK)-mediated elimination of tumor cells is mostly dependent on Granzyme B apoptotic pathway, which is regulated by the wild type (wt) p53 protein. Because TP53 inactivating mutations, frequently found in human tumors, could interfere with Granzyme B-mediated cell death, the use of small molecules developed to reactivate wtp53 function in p53-mutated tumor cells could optimize their lysis by CTL or NK cells. Here, we show that the pharmalogical reactivation of a wt-like p53 function in p53-mutated breast cancer cells using the small molecule CP-31398 increases their sensitivity to NK-mediated lysis. This potentiation is dependent on p53-mediated induction of autophagy via the sestrin-AMPK-mTOR pathway and the ULK axis. This CP31398-induced autophagy sequestrates in autophagosomes several anti-apoptotic proteins, including Bcl-XL and XIAP, facilitating Granzyme B-mediated mitochondrial outer membrane permeabilization, caspase-3 activation and Granzyme B- or NK cell-induced apoptosis. Together, our results define a new way to increase cytotoxic lymphocyte-mediated lysis of p53-mutated breast cancer cell, through a p53-dependent autophagy induction, with potential applications in combined immunotherapeutic approaches.

Des concepts différents, dérivés de celui d'entropie, mais qui s'y opposent, seront corrélés dans l'analyse de l'état vivant de la matière : ceux de neguentropie et d'anti-entropie. On discutera le rôle disruptif de l'entropie ainsi que son apport à la production de l'organisation du vivant (anti-entropie), dans l'espace et dans le temps. Cela nous permettra de parler de l'historicité du vivant et de définir un espace de viabilité où la diversité anti-entropique est obtenue par intégration/assimilation d'entropie locale (variation) dans les structures spatiales et les rythmes temporels du vivant. Le local co-construit ainsi le global, tout en constituant une contrainte de l'un sur l'autre, dans une tension au coeur de la phylogenèse et de l'ontogenèse. ABSTRACT. Different concepts, derived from that of entropy, but which oppose it, will be correlated in the analysis of the living state of matter: those of negentropy and anti-entropy. We will discuss the disruptive role of entropy as well as its contribution to the production of the organization of life (anti-entropy), in space and time. This will allow us to talk about the historicity of the living and to define a space of viability where anti-entropic diversity is obtained by integration/assimilation of local entropy (variation) in the spatial structures and temporal rhythms of the living. The local thus co-constructs the global, while they constitute a constraint of one on the other, in a tension at the heart of phylogenesis and ontogenesis.

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