Immune cell - produced ROS and their impact on tumor growth and metastasis

Abstract

Reactive oxygen species (ROS) are derivatives of molecular oxygen (O 2 ) involved in various physiological and pathological processes. In immune cells, ROS are mediators of pivotal functions such as phagocytosis, antigen presentation and recognition, cytolysis as well as phenotypical differentiation. Furthermore, ROS exert immunosuppressive effects on T and natural killer (NK) cells which is of particular importance in the so-called “tumor microenvironment” (TME) of solid tumors. This term describes the heterogenous group of non-malignant cells including tumor-associated fibroblasts and immune cells, vascular cells, bacteria etc. by which cancer cells are surrounded and with whom they engage in functional crosstalk. Importantly, pharmacological targeting of the TME and, specifically, tumor-associated immune cells utilizing immune checkpoint inhibitors - monoclonal antibodies that mitigate immunosuppression - turned out to be a major breakthrough in the treatment of malignant tumors. In this review, we aim to give an overview of the role that ROS produced in tumor-associated immune cells play during initiation, progression and metastatic outgrowth of solid cancers. Finally, we summarize findings on how ROS in the TME could be targeted therapeutically to increase the efficacy of cancer immunotherapy and discuss factors determining therapeutic success of redox modulation in tumors.

Role of the Inflammatory Response of RAW 264.7 Cells in the Metastasis of Novel Cancer Stem-Like Cells

“…The levels of ROS production have been reported to be correlated with not only tumor metastasis but also most disease processes [ 20 ]. Moderate ROS production in tumor cells can cause pathological conditions and promote tumor formation and progression via increases in the metabolic rate, DNA mutation, and angiogenesis, and excess ROS can be eliminated by increased activity of antioxidant pathways in redox-adapted cancer cells.…”

Microenvironmental Reactive Oxygen Species in Colorectal Cancer: Involved Processes and Therapeutic Opportunities

“…Among all these entities, tumor cells and immune cells such as macrophages and neutrophils are major ROS producers; however, there are other minor ROS sources worth consideration (Figure 1). Depending on the type of ROS-producing cell the consequences are different and can be either tumor-supportive or tumor-suppressive [4].…”

“…M1 macrophages are generally considered to be tumor-killing macrophages, while M2 macrophages promote tumor growth and metastasis and are associated with poor prognosis. ROS can stimulate activation statuses in tumor-associated macrophages (TAMs) [4]. Besides, the ROS scavengers N-acetylcysteine and the NADPH oxidase ROS inhibitor diphenyleneiodonium induce monocyte polarization toward M1-like macrophages and the repolarization of M2 macrophages into M1 phenotypes.…”

“…Cancers are not just clonal masses of malignant cells but involve the intricate cooperation of many other cell types which are recruited and can be corrupted by the trans-formed ones, creating the tumor microenvironment (TME) [3]. Cells from the TME, like macrophages, neutrophils, and fibroblasts, are sources of growth factors, cytokines, proteases, and reactive oxygen species (ROS) that modify the cancer niche, acting on multiple cell types and matrix components [4].…”

Neutrophils in Tumorigenesis: Missing Targets for Successful Next Generation Cancer Therapies?

“…• TRPM2 activation → lethal Ca 2+ entry [21] Tumor growth inhibition ROS production • DNA mutations [22] Tumor promotion /progression Chemokine/cytokine secretion…”