Reactive oxygen species (ROS) are derivatives of molecular oxygen (O2) 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.
Standard cancer therapy targets tumor cells without considering possible damage on the tumor microenvironment that could impair therapy response. In rectal cancer patients we find that inflammatory ...cancer-associated fibroblasts (iCAFs) are associated with poor chemoradiotherapy response. Employing a murine rectal cancer model or patient-derived tumor organoids and primary stroma cells, we show that, upon irradiation, interleukin-1α (IL-1α) not only polarizes cancer-associated fibroblasts toward the inflammatory phenotype but also triggers oxidative DNA damage, thereby predisposing iCAFs to p53-mediated therapy-induced senescence, which in turn results in chemoradiotherapy resistance and disease progression. Consistently, IL-1 inhibition, prevention of iCAFs senescence, or senolytic therapy sensitizes mice to irradiation, while lower IL-1 receptor antagonist serum levels in rectal patients correlate with poor prognosis. Collectively, we unravel a critical role for iCAFs in rectal cancer therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of cancer-associated fibroblasts senescence.
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•Inflammatory CAFs are associated with poor prognosis in rectal cancer•Oxidative DNA damage in iCAFs is a pre-requisite for irradiation-induced senescence•IL-1 inhibition prevents iCAF senescence upon irradiation, improving therapy response•IL-1 signaling is enhanced by low serum IL-1RA in patients with poor prognosis
Nicolas et al. highlight the important role of inflammatory cancer-associated fibroblasts (iCAFs) for therapy response of rectal cancer patients. They demonstrate that IL-1-dependent signaling elevates oxidative DNA damage in iCAFs, which upon irradiation undergo senescence. This causes tissue remodeling and therapy resistance that can be overcome by inhibiting IL-1.
Tumor-associated inflammation (TAI) is a feature of essentially all cancers and can confer both tumor-promoting and -suppressive functions. Cancer-associated fibroblasts (CAF) comprise one very ...heterogeneous cellular component of the tumor microenvironment characterized by a high degree of plasticity. Recent single-cell sequencing analyses revealed distinct CAF populations in various human cancers and helped to define key CAF subtypes, such as myofibroblastic, inflammatory, and antigen-presenting CAFs, with the first two being present in virtually all tumors. Importantly, these three CAF populations are involved in and modulate the positive and negative consequences of TAI. The remarkable plasticity of CAFs allows them to shift phenotypically and functionally in response to environmental changes. In this review, we describe how CAFs nurture tumor-promoting inflammation and suppress adaptive immunity. We also summarize the recently emerging evidence pertaining to tumor-suppressive CAF functions in the context of TAI. Finally, we summarize therapeutic concepts that aim at modulating CAF functions or depleting immunosuppressive CAFs to synergize with immunotherapy.
The PHD1 oxygen sensor in health and disease Kennel, Kilian B.; Burmeister, Julius; Schneider, Martin ...
The Journal of physiology,
1 September 2018, Letnik:
596, Številka:
17
Journal Article
Recenzirano
Odprti dostop
The hypoxia‐inducible factor (HIF) co‐ordinates the adaptive transcriptional response to hypoxia in metazoan cells. The hypoxic sensitivity of HIF is conferred by a family of oxygen‐sensing enzymes ...termed HIF hydroxylases. This family consists of three prolyl hydroxylases (PHD1–3) and a single asparagine hydroxylase termed factor inhibiting HIF (FIH). It has recently become clear that HIF hydroxylases are functionally non‐redundant and have discrete but overlapping physiological roles. Furthermore, altered abundance or activity of these enzymes is associated with a number of pathologies. Pharmacological HIF‐hydroxylase inhibitors have recently proven to be both tolerated and therapeutically effective in patients. In this review, we focus on the physiology, pathophysiology and therapeutic potential of the PHD1 isoform, which has recently been implicated in diseases including inflammatory bowel disease, ischaemia and cancer.
PHD1 expression and activity are under the control of a range of stimuli including molecular oxygen, metabolites, microRNAs and post‐translational modifications (PTMs). PHD1, through hydroxylation, regulates the activity of pathways including the hypoxia inducible factor (HIF) and nuclear factor‐κB (NF‐κB), which in turn regulate processes including inflammation, ischaemia and tumour growth.
Solid cancers exhibit a dynamic balance between cell death and proliferation ensuring continuous tumour maintenance and growth
. Increasing evidence links enhanced cancer cell apoptosis to paracrine ...activation of cells in the tumour microenvironment initiating tissue repair programs that support tumour growth
, yet the direct effects of dying cancer cells on neighbouring tumour epithelia and how this paracrine effect potentially contributes to therapy resistance are unclear. Here we demonstrate that chemotherapy-induced tumour cell death in patient-derived colorectal tumour organoids causes ATP release triggering P2X4 (also known as P2RX4) to mediate an mTOR-dependent pro-survival program in neighbouring cancer cells, which renders surviving tumour epithelia sensitive to mTOR inhibition. The induced mTOR addiction in persisting epithelial cells is due to elevated production of reactive oxygen species and subsequent increased DNA damage in response to the death of neighbouring cells. Accordingly, inhibition of the P2X4 receptor or direct mTOR blockade prevents induction of S6 phosphorylation and synergizes with chemotherapy to cause massive cell death induced by reactive oxygen species and marked tumour regression that is not seen when individually applied. Conversely, scavenging of reactive oxygen species prevents cancer cells from becoming reliant on mTOR activation. Collectively, our findings show that dying cancer cells establish a new dependency on anti-apoptotic programs in their surviving neighbours, thereby creating an opportunity for combination therapy in P2X4-expressing epithelial tumours.
In colorectal cancers (CRC) the tumor microenvironment plays a key role for prognosis and therapy efficacy. Patient-derived tumor organoids (PDTOs) show enormous potential for preclinical testing, ...however, cultured tumor cells lose important characteristics including the 'consensus molecular subtypes' (CMS). To better reflect the cellular heterogeneity, we established the CRC organoid-stroma biobank of matched PDTOs and cancer-associated fibroblasts (CAFs) from 30 patients. Context-specific phenotyping showed that xenotransplantation or co-culture with CAFs improves the transcriptomic fidelity and instructs subtype-specific stromal gene expression. Furthermore, functional profiling in co-culture exposed CMS4-specific therapeutic resistance to Gefitinib and SN-38 and prognostic expression signatures. Chemogenomic library screening identified patient- and therapy-dependent mechanisms of stromal resistance including MET as common target. Our results demonstrate that CRC phenotypes are encrypted in the cancer epithelium in a plastic fashion that strongly depends on the context. Consequently, CAFs are essential for faithful representation of molecular subtypes and therapy responses ex vivo.
Colitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD). HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) control cellular adaptation to hypoxia and are ...considered promising therapeutic targets in IBD. However, their relevance in the pathogenesis of CAC remains elusive. We induced CAC in Phd1-/-, Phd2+/-, Phd3-/-, and WT mice with azoxymethane (AOM) and dextran sodium sulfate (DSS). Phd1-/- mice were protected against chronic colitis and displayed diminished CAC growth compared with WT mice. In Phd3-/- mice, colitis activity and CAC growth remained unaltered. In Phd2+/- mice, colitis activity was unaffected, but CAC growth was aggravated. Mechanistically, Phd2 deficiency (i) increased the number of tumor-associated macrophages in AOM/DSS-induced tumors, (ii) promoted the expression of EGFR ligand epiregulin in macrophages, and (iii) augmented the signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 signaling, which at least in part contributed to aggravated tumor cell proliferation in colitis-associated tumors. Consistently, Phd2 deficiency in hematopoietic (Vav:Cre-Phd2fl/fl) but not in intestinal epithelial cells (Villin:Cre-Phd2fl/fl) increased CAC growth. In conclusion, the 3 different PHD isoenzymes have distinct and nonredundant effects, promoting (PHD1), diminishing (PHD2), or neutral (PHD3), on CAC growth.
We demonstrate that PHD1 is overexpressed in pouchitis in patients with ulcerative colitis and correlates with disease activity. PHD small-molecule inhibition mitigates pouchitis in a preclinical ...rodent IPAA model, thus establishing a strong therapeutic rationale for targeting PHD1 in pouchitis.
Abstract
Background
Pouchitis is the most common long-term complication after restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) for ulcerative colitis (UC) or familial adenomatous polyposis (FAP), which can eventually progress to pouch failure, necessitating permanent stoma construction. Hypoxia-inducible transcription factor prolyl hydroxylase–containing enzymes (PHD1, PHD2, and PHD3) are molecular oxygen sensors that control adaptive gene expression through hypoxia-inducible factor (HIF). Emerging evidence supports PHDs as being therapeutic targets in intestinal inflammation. However, pharmacological inhibition of PHDs has not been validated as a treatment strategy in pouchitis.
Methods
PHD1-3 mRNA and protein expression were analyzed in mucosal pouch and prepouch ileal patient biopsies. After establishment of a preclinical IPAA model in rats, the impact of the pan-PHD small-molecule inhibitor dimethyloxalylglycine (DMOG) on dextran sulfate sodium (DSS)–induced pouchitis was studied. Clinical and molecular parameters were investigated.
Results
PHD1, but not PHD2 or PHD3, was overexpressed in pouchitis in biopsies of patients with IPAA for UC but not FAP. In addition, PHD1 expression correlated with disease activity. DMOG treatment profoundly mitigated DSS-induced pouchitis in a rodent IPAA model. Mechanistically, DMOG restored intestinal epithelial barrier function by induction of tight junction proteins zona occludens-1 and claudin-1 and alleviation of intestinal epithelial cell apoptosis, thus attenuating pouch inflammation.
Conclusions
Together, these results establish a strong therapeutic rationale for targeting PHD1 with small-molecule inhibitors in pouchitis after IPAA for UC.
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