Modulating Both Tumor Cell Death and Innate Immunity Is Essential for Improving Radiation Therapy Effectiveness

Radiation therapy is one of the cornerstones of cancer treatment. In tumor cells, exposure to ionizing radiation (IR) provokes DNA damages that trigger various forms of cell death such as apoptosis, necrosis, autophagic cell death, and mitotic catastrophe. IR can also induce cellular senescence that could serve as an additional antitumor barrier in a context-dependent manner. Moreover, accumulating evidence has demonstrated that IR interacts profoundly with tumor-infiltrating immune cells, which cooperatively drive treatment outcomes. Recent preclinical and clinical successes due to the combination of radiation therapy and immune checkpoint blockade have underscored the need for a better understanding of the interplay between radiation therapy and the immune system. In this review, we will present an overview of cell death modalities induced by IR, summarize the immunogenic properties of irradiated cancer cells, and discuss the biological consequences of IR on innate immune cell functions, with a particular attention on dendritic cells, macrophages, and NK cells. Finally, we will discuss their potential applications in cancer treatment

Anticancer chemotherapy and radiotherapy trigger both non-cell-autonomous and cell-autonomous death.

Even though cell death modalities elicited by anticancer chemotherapy and radiotherapy have been extensively studied, the ability of anticancer treatments to induce non-cell-autonomous death has never been investigated. By means of multispectral imaging flow-cytometry-based technology, we analyzed the lethal fate of cancer cells that were treated with conventional anticancer agents and co-cultured with untreated cells, observing that anticancer agents can simultaneously trigger cell-autonomous and non-cell-autonomous death in treated and untreated cells. After ionizing radiation, oxaliplatin, or cisplatin treatment, fractions of treated cancer cell populations were eliminated through cell-autonomous death mechanisms, while other fractions of the treated cancer cells engulfed and killed neighboring cells through non-cell-autonomous processes, including cellular cannibalism. Under conditions of treatment with paclitaxel, non-cell-autonomous and cell-autonomous death were both detected in the treated cell population, while untreated neighboring cells exhibited features of apoptotic demise. The transcriptional activity of p53 tumor-suppressor protein contributed to the execution of cell-autonomous death, yet failed to affect the non-cell-autonomous death by cannibalism for the majority of tested anticancer agents, indicating that the induction of non-cell-autonomous death can occur under conditions in which cell-autonomous death was impaired. Altogether, these results reveal that chemotherapy and radiotherapy can induce both non-cell-autonomous and cell-autonomous death of cancer cells, highlighting the heterogeneity of cell death responses to anticancer treatments and the unsuspected potential contribution of non-cell-autonomous death to the global effects of anticancer treatment

Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection

Contact with HIV-1 envelope protein elicits release of ATP through pannexin-1 channels on target cells; by activating purinergic receptors and Pyk2 kinase in target cells, this extracellular ATP boosts HIV-1 infectivity

Etude des mécanismes moléculaires de la régulation fonctionnelle d'AIF

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocSudocFranceF

CHCHD4 links AIF to the biogenesis of respiratory chain complex I

International audienc

Exploring the contribution of the mitochondrial disulfide relay system to Parkinson’s disease: the PINK1/CHCHD4 interplay

International audienc

A human mitochondriopathy caused by AIF mutation

International audienc

Mitochondrial Proteins Containing Coiled-Coil-Helix-Coiled-Coil-Helix (CHCH) Domains in Health and Disease

International audienc

Apoptosis-inducing factor: vital and lethal

International audienceApoptosis-inducing factor (AIF) is a NADH oxidase with a local redox function that is essential for optimal oxidative phosphorylation and for an efficient anti-oxidant defense. The absence of AIF can cause neurodegeneration, skeleton muscle atrophy and dilated cardiomyopathy. In many models of apoptosis, AIF translocates to the nucleus, where it induces chromatin condensation and DNA degradation. The nuclear localization of AIF can be inhibited by blocking upstream signals of apoptosis. The contribution of AIF to cell death depends on the cell type and apoptotic insult and is only seen when caspases are inhibited or not activated. It is unknown to what extent and through which mechanisms AIF contributes to the induction of cell death. Here, we discuss recent progress in the quest to understand the contribution of AIF to life and death