bims-noxint 2022-07-10 papers

Issue of 2022–07–10
two papers selected by
Laia Caja Puigsubira, Uppsala University

Curr Drug Targets. 2022 Jul 05.

Redox interactions in chemo/radiation therapy-induced lung toxicity; mechanisms and therapy perspectives.

Lung toxicity is a key limiting factor for the therapy of cancer, especially lung, breast, and esophageal malignancies. Radiotherapy for chest and breast malignancies can cause lung injury. However, systemic cancer therapy with chemotherapy also may induce lung pneumonitis and fibrosis. Radiotherapy produces reactive oxygen species (ROS) directly via interacting with water molecules within cells. However, radiation and other therapy modalities may induce the endogenous generation of ROS and nitric oxide (NO) by immune cells and some nonimmune cells such as fibroblasts and endothelial cells. There are several ROS generating enzymes within lung tissue. NADPH Oxidase enzymes, cyclooxygenase-2 (COX-2), dual oxidases (DUOX1 and DUOX2), and the cellular respiratory system in the mitochondria are the main sources of ROS production following exposure of the lung to anticancer agents. Furthermore, inducible nitric oxide synthase (iNOS) has a key role in the generation of NO following radiotherapy or chemotherapy. Continuous generation of ROS and NO by endothelial cells, fibroblasts, macrophages, and lymphocytes causes apoptosis, necrosis, and senescence, which lead to the release of inflammatory and pro-fibrosis cytokines. This review discusses the cellular and molecular mechanisms of redox-induced lung injury following cancer therapy and proposes some targets and perspectives to alleviate lung toxicity.

Keywords: Fibrosis; Lung; Pneumonitis; Reactive Oxygen Species (ROS); Reduction/oxidation (Redox)

DOI: https://doi.org/10.2174/1389450123666220705123315

Front Immunol. 2022 ;13 899068

CD47-SIRPα Controls ADCC Killing of Primary T Cells by PMN Through a Combination of Trogocytosis and NADPH Oxidase Activation.

Françoise Gondois-Rey, Thomas Miller, Vladimir Laletin, Xavier Morelli, Yves Collette, Jacques Nunès, Daniel Olive.

Immunotherapies targeting the "don't eat me" myeloid checkpoint constituted by CD47 SIRPα interaction have promising clinical potential but are limited by toxicities associated with the destruction of non-tumor cells. These dose-limiting toxicities demonstrate the need to highlight the mechanisms of anti-CD47-SIRPα therapy effects on non-tumor CD47-bearing cells. Given the increased incidence of lymphopenia in patients receiving anti-CD47 antibodies and the strong ADCC (antibody-dependent cellular cytotoxicity) effector function of polymorphonuclear cells (PMNs), we investigated the behavior of primary PMNs cocultured with primary T cells in the presence of anti-CD47 mAbs. PMNs killed T cells in a CD47-mAb-dependent manner and at a remarkably potent PMN to T cell ratio of 1:1. The observed cytotoxicity was produced by a novel combination of both trogocytosis and a strong respiratory burst induced by classical ADCC and CD47-SIRPα checkpoint blockade. The complex effect of the CD47 blocking mAb could be recapitulated by combining its individual mechanistic elements: ADCC, SIRPα blockade, and ROS induction. Although previous studies had concluded that disruption of SIRPα signaling in PMNs was limited to trogocytosis-specific cytotoxicity, our results suggest that SIRPα also tightly controls activation of NADPH oxidase, a function demonstrated during differentiation of immature PMNs but not so far in mature PMNs. Together, our results highlight the need to integrate PMNs in the development of molecules targeting the CD47-SIRPα immune checkpoint and to design agents able to enhance myeloid cell function while limiting adverse effects on healthy cells able to participate in the anti-tumor immune response.

Keywords: ADCC (antibody-dependent cellular cytotoxicity); CD47 antibody; NADPH oxidase; PMN (polymorphonuclear leucocyte); SIRPα

DOI: https://doi.org/10.3389/fimmu.2022.899068