Reactive oxygen species: Janus-faced molecules in the era of modern cancer therapy

Abstract

Oxidative stress, that is, an unbalanced increase in reactive oxygen species (ROS), contributes to tumor-induced immune suppression and limits the efficacy of immunotherapy. Cancer cells have inherently increased ROS production, intracellularly through metabolic perturbations and extracellularly through activation of NADPH oxidases, which promotes cancer progression. Further increased ROS production or impaired antioxidant systems, induced, for example, by chemotherapy or radiotherapy, can preferentially kill cancer cells over healthy cells. Inflammatory cell-derived ROS mediate immunosuppressive effects of myeloid-derived suppressor cells and activated granulocytes, hampering antitumor effector cells such as T cells and natural killer (NK) cells. Cancer therapies modulating ROS levels in tumors may thus have entirely different consequences when targeting cancer cells versus immune cells. Here we discuss the possibility of developing more efficient cancer therapies based on reduction-oxidation modulation, as either monotherapies or in combination with immunotherapy. Short-term, systemic administration of antioxidants or drugs blocking ROS production can boost the immune system and act in synergy with immunotherapy. However, prolonged use of antioxidants can instead enhance tumor progression. Alternatives to systemic antioxidant administration are under development where gene-modified or activated T cells and NK cells are shielded ex vivo against the harmful effects of ROS before the infusion to patients with cancer.

Keywords: Immune modulatory; Immunosuppression; Immunotherapy; Tumor microenvironment - TME.

Figure 1. Hypothesis regarding redox modulation for efficient cancer therapy. This simplified scheme illustrates how reactive oxygen species (ROS; red stars) can play different roles at different levels in cancer, and how we propose that directed redox modulation may be used to achieve more efficient therapy outcome. Typically, cancer cells and stroma of the tumor microenvironment (right half of the figure, blue background) promote the accumulation of higher ROS levels that hamper the functionality of immune effector cells (left half of the figure, orange background), including dendritic cells, natural killer cells (NK cells), B cells, and cytotoxic T cells. Additionally, immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs) and regulatory T cells, exert negative control over immune effector cells through ROS-dependent mechanisms. In the context of tumor therapy, further increased oxidation in cancer cells can trigger intolerable levels of ROS, leading to either immunogenic cell death (ICD) or non-ICD. ICD, in particular, can give release of damage-associated molecular patterns (DAMPs) further promoting adaptive immune responses. A therapeutic use of antioxidants or the deliberate increase of endogenous antioxidant systems in immune effector cells rendering them more resistant to ROS can improve their efficacy. A combination of approaches resulting in an increase of ROS levels in cancer cells and the improved resistance to ROS in immune effector cells may have the potential to synergistically enhance the efficacy of cancer therapy. Green arrows: redox modulatory processes supporting cancer therapy. Red arrows: redox modulatory processes counteracting efficient therapeutic outcome in cancer therapy. Figure created with BioRender. See table 1 and the main text for further details.

Figure 2. (A) ROS are essential for normal inflammation and the immune response. The interaction between the MHC-antigen complex and the TCR generates ROS facilitating T-cell activation and expansion. High levels of environmental ROS favor Th2 cellular differentiation. ROS contributes to activation-induced cell death via induction of FasL expression facilitating T-cell contraction. ROS are essential for antimicrobial killing by phagocytes via the oxidative burst and NLRP3 inflammasome activation. ROS are implicated in both the M1 and M2 macrophage polarization. ROS participate in neutrophil extracellular traps construction, release and NETosis. ROS partake in dendritic cell (DC) differentiation, maturation, activation and DC secretory function. DC-derived ROS is indispensable in antigen presentation and cross-presentation. (B). Oxidative stress in the TME facilitates immunosuppression. ROS contributes to the maintenance of MDSCs in an undifferentiated state. MDSCs are a source of various ROS including peroxynitrite (ONOO⁻), myeloperoxidase (MPO) and hydrogen peroxide (H₂O₂). Ferroptotic PMN-MDSCs release immunosuppressive factors, including peroxidized lipids and PGE2. ROS facilitate the acquisition of an immunosuppressive tumor promoting “M2-like” TAM phenotype. TME oxidative stress promotes dendritic cell dysfunction and impairs intratumoral DCs. ROS can facilitate Treg stability and immunosuppression. ROS can induce Treg apoptosis. Apoptotic tumor-associated Tregs release ATP that is metabolized to adenosine via CD39 and CD73 limiting antitumor immunity via the A2A pathway. ROS can reduce T-cell expression of CD3ζ and IFN-γ. ROS induce nitration of the TCR-CD8 complex and impair trafficking of antigen-specific T-cells via CCL2 nitration and alteration of the MHC class I peptidome presented by tumors diminished immunogenicity. TME elevated intrinsic ROS drives the induction of terminally exhausted T cells. TME ROS promote apoptosis of NK cells. IFN, interferon; IL, interleukin; CCL2 chemokine ligand 2, MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; NK, natural killer; NLRP3 NOD-, LRR- and pyrin domain-containing protein 3, PG2 prostaglandin E2, PMN-MDSC, polymorphonuclear MDSC; ROS, reactive oxygen species; TAM, tumor associated macrophage; TCR T-cell receptor, TME, tumor microenvironment; Treg, regulatory T cells. Figure created with BioRender.