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Review
. 2020 Jul 21:11:1538.
doi: 10.3389/fimmu.2020.01538. eCollection 2020.

cROSsing the Line: Between Beneficial and Harmful Effects of Reactive Oxygen Species in B-Cell Malignancies

Krzysztof Domka  1 , Agnieszka Goral  1 , Malgorzata Firczuk  1
Affiliations
Review

cROSsing the Line: Between Beneficial and Harmful Effects of Reactive Oxygen Species in B-Cell Malignancies

Krzysztof Domka et al. Front Immunol. .

Abstract

B-cell malignancies are a heterogeneous group of hematological neoplasms derived from cells at different stages of B-cell development. Recent studies revealed that dysregulated redox metabolism is one of the factors contributing to the pathogenesis and progression of B-cell malignancies. Elevated levels of oxidative stress markers usually correlate with the advanced stage of various B-cell malignancies. In the complex tumor microenvironment, reactive oxygen species affect not only malignant cells but also bystander cells, including immune cells. Importantly, malignant cells, due to genetic dysregulation, are able to adapt to the increased demands for energy and reducing equivalents via metabolic reprogramming and upregulation of antioxidants. The immune cells, however, are more sensitive to oxidative imbalance. This may cause their dysfunction, leading to immune evasion and tumor progression. On the other hand, the already imbalanced redox homeostasis renders malignant B-cells particularly sensitive to further elevation of reactive oxygen species. Indeed, targeting antioxidant systems has already presented anti-leukemic efficacy in preclinical models. Moreover, the prooxidant treatment that triggers immunogenic cell death has been utilized to generate autologous anti-leukemic vaccines. In this article, we review novel research on the dual role of the reactive oxygen species in B-cell malignancies. We highlight the mechanisms of maintaining redox homeostasis by malignant B-cells along with the antioxidant shield provided by the microenvironment. We summarize current findings regarding therapeutic targeting of redox metabolism in B-cell malignancies. We also discuss how the oxidative stress affects antitumor immune response and how excessive reactive oxygens species influence anticancer prooxidant treatments and immunotherapies.

Keywords: B-ALL; B-cell malignancies; CLL; ROS; immune evasion; leukemia; lymphoma; oxidative stress.

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Figures

Figure 1
Figure 1
Oxidative stress displays a dual role in the fate of B-cell malignancies. The ultimate outcome of redox imbalance on B-cell malignancies depends on the source, concentration, location of reactive oxygen species (ROS), as well as the duration of exposure. Importantly, the overall effect of ROS on the fate of B-cell neoplasms depends on the action of ROS both on malignant B-cells and on the cells of the TME, including immune cells. However, malignant cells adapt to the increased demands for energy and reducing equivalents by increasing their antioxidant capacity and rewiring their metabolic energy pathways, which renders them therapy-resistant [1]. At the same time, the highly oxidative microenvironment may negatively affect function of the effector immune cells, causing impairment of antitumor immune response, contributing to immune evasion and further tumor progression [2]. Conversely, targeting specific antioxidant pathways in malignant B cells or inhibiting the antioxidant support provided by the TME trigger direct, oxidative-stress mediated cytotoxicity and can effectively eradicate malignant B cells [3]. Moreover, some forms of oxidative stress-mediated cell death under certain conditions are immunogenic. This leads to the activation of immune cells and subsequent development of antitumor response, what further contributes to the efficacy of prooxidant treatments [4]. The figure was created using BioRender.com.
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