Chronic inflammation generated by the tumor microenvironment is known to drive cancer initiation, proliferation, progression, metastasis, and therapeutic resistance. The tumor microenvironment ...promotes the secretion of diverse cytokines, in different types and stages of cancers. These cytokines may inhibit tumor development but alternatively may contribute to chronic inflammation that supports tumor growth in both autocrine and paracrine manners and have been linked to poor cancer outcomes. Such distinct sets of cytokines from the tumor microenvironment can be detected in the circulation and are thus potentially useful as biomarkers to detect cancers, predict disease outcomes and manage therapeutic choices. Indeed, analyses of circulating cytokines in combination with cancer-specific biomarkers have been proposed to simplify and improve cancer detection and prognosis, especially from minimally-invasive liquid biopsies, such as blood. Additionally, the cytokine signaling signatures of the peripheral immune cells, even from patients with localized tumors, are recently found altered in cancer, and may also prove applicable as cancer biomarkers. Here we review cytokines induced by the tumor microenvironment, their roles in various stages of cancer development, and their potential use in diagnostics and prognostics. We further discuss the established and emerging diagnostic approaches that can be used to detect cancers from liquid biopsies, and additionally the technological advancement required for their use in clinical settings.
Regulatory T cells (Tregs) have been shown to play a role in the development of solid tumors. A better understanding of the biology of Tregs, immune suppression by Tregs, and how cancer developed ...with the activity of Tregs has facilitated the development of strategies used to improve immune-based therapy. In ovarian cancer, Tregs have been shown to promote cancer development and resistance at different cancer stages. Understanding the various Treg-mediated immune escape mechanisms provides opportunities to establish specific, efficient, long-lasting anti-tumor immunity. Here, we review the evidence of Treg involvement in various stages of ovarian cancer. We further provide an overview of the current and prospective therapeutic approaches that arise from the modulation of Treg-related tumor immunity at those specific stages. Finally, we propose combination strategies of Treg-related therapies with other anti-tumor therapies to improve clinical efficacy and overcome tumor resistance in ovarian cancer.
Ovarian cancer (OC) is one of the most lethal cancers, largely due to a late diagnosis. This study aimed to provide a comprehensive meta-analysis on the diagnostic performance of IL6 in the blood and ...ascites separately for advanced and early-stage OC. We included 37 studies with 6948 participants detecting serum or plasma IL6. The plasma/serum IL6 mean level in the late-stage OC was 23.88 pg/mL (95% CI: 13.84-41.23), and the early-stage OC was 16.67 pg/mL (95% CI: 510.06-27.61), significantly higher than the healthy controls at 3.96 pg/mL (95% CI: 2.02-7.73), but not significantly higher than those found in the controls with benign growths in the ovary, which was 9.63 pg/mL (95% CI: 4.16-22.26). To evaluate IL6 in ascites as a diagnostic marker, we included 26 studies with 1590 participants. The mean level of ascitic IL6 in the late-stage OC was 3676.93 pg/mL (95% CI: 1891.7-7146.7), and the early-stage OC was 1519.21 pg/mL (95% CI: 604.6-3817.7), significantly higher than the benign controls at 247.33 pg/mL (95% CI: 96.2-636.0). There was no significant correlation between the levels of circulating and ascitic IL6. When pooling all OC stages for analysis, we found that serum/plasma IL6 provided 76.7% sensitivity (95% CI: 0.71-0.92) and 72% specificity (95% CI: 0.64-0.79). Ascitic IL6 provided higher sensitivity at 84% (95% CI: 0.710-0.919) and specificity at 74% (95% CI: 0.646-0.826). This study highlights the utility of ascitic IL6 for early detection of OC.
High Tumor Necrosis Factor Receptor 2 (TNFR2) expression is characteristic of diverse malignant cells during tumorigenesis. The protein is also expressed by many immunosuppressive cells during cancer ...development, allowing cancer immune escape. A growing body of evidence further suggests a correlation between the circulating form of this protein and cancer development. Here we conducted a systematic meta-analysis of cancer studies published up until 1
October 2022, in which the circulating soluble TNFR2 (sTNFR2) concentrations in patients with cancers were recorded and their association with cancer risk was assessed. Of the 14,615 identified articles, 44 studies provided data on the correlation between cancer risk and the level of circulating sTNFR2. The pooled means comparison showed a consistently significant increase in the levels of sTNFR2 in diverse cancers when compared to healthy controls. These included colorectal cancer, ovarian cancer, breast cancer, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer, hepatocarcinoma, and glioblastoma. In a random-effect meta-analysis, the cancer-specific odd ratios (OR) showed significant correlations between increased circulating sTNFR2 levels and the risk of colorectal cancer, non-Hodgkin's lymphoma, and hepatocarcinoma at 1.59 (95% CI:1.20-2.11), 1.98 (95% CI:1.49-2.64) and 4.32 (95% CI:2.25-8.31) respectively. The overall result showed an association between circulating levels of sTNFR2 and the risk of developing cancer at 1.76 (95% CI:1.53-2.02). This meta-analysis supports sTNFR2 as a potential diagnostic biomarker for cancer, albeit with different predictive strengths for different cancer types. This is consistent with a potential key role for TNFR2 involvement in cancer development.
Many cancers are predominantly diagnosed in older individuals and chronic inflammation has a major impact on the overall health and immune function of older cancer patients. Chronic inflammation is a ...feature of aging, it can accelerate disease in many cancers and it is often exacerbated during conventional treatments for cancer. This review will provide an overview of the factors that lead to increased inflammation in older individuals and/or individuals with cancer, as well as those that result from conventional treatments for cancer, using ovarian cancer (OC) and multiple myeloma (MM) as key examples. We will also consider the impact of chronic inflammation on immune function, with a particular focus on T cells as they are key targets for novel cancer immunotherapies. Overall, this review aims to highlight specific pathways for potential interventions that may be able to mitigate the impact of chronic inflammation in older cancer patients.
Age‐, disease‐ and treatment‐driven inflammation can all limit T cell function in older cancer patients and this should be a critical consideration for T cell‐targeted immunotherapies.
Ovarian cancer (OC) is one of the most common, and life-threatening gynaecological cancer affecting females. Almost 75% of all OC cases are diagnosed at late stages, where the 5-year survival rate is ...less than 30%. The aetiology of the disease is still unclear, and there are currently no screening method nor effective treatment strategies for the advanced disease. A growing body of evidence shows that human cytomegalovirus (HCMV) infecting more than 50% of the world population, may play a role in inducing carcinogenesis through its immunomodulatory activities. In healthy subjects, the primary HCMV infection is essentially asymptomatic. The virus then establishes a life-long chronic latency primarily in the hematopoietic progenitor cells in the bone marrow, with periodic reactivation from latency that is often characterized by high levels of circulating pro-inflammatory cytokines. Currently, infection-induced chronic inflammation is considered as an essential process for OC progression and metastasis. In line with this observation, few recent studies have identified high expressions of HCMV proteins on OC tissue biopsies that were associated with poor survival outcomes. Active HCMV infection in the OC tumour microenvironment may thus directly contribute to OC progression. In this review, we highlight the potential impact of HCMV infection-induced immunomodulatory effects on host immune responses to OC that may promote OC progression.
High-grade serous ovarian carcinoma (HGSOC) is a genomically unstable malignancy responsible for over 70% of all deaths due to ovarian cancer. With roughly 50% of all HGSOC harboring defects in the ...homologous recombination (HR) DNA repair pathway (e.g.,
BRCA1/
2 mutations), the introduction of poly ADP-ribose polymerase inhibitors (PARPi) has dramatically improved outcomes for women with HR defective HGSOC. By blocking the repair of single-stranded DNA damage in cancer cells already lacking high-fidelity HR pathways, PARPi causes the accumulation of double-stranded DNA breaks, leading to cell death. Thus, this synthetic lethality results in PARPi selectively targeting cancer cells, resulting in impressive efficacy. Despite this, resistance to PARPi commonly develops through diverse mechanisms, such as the acquisition of secondary
BRCA1/2
mutations. Perhaps less well documented is that PARPi can impact both the tumour microenvironment and the immune response, through upregulation of the stimulator of interferon genes (STING) pathway, upregulation of immune checkpoints such as PD-L1, and by stimulating the production of pro-inflammatory cytokines. Whilst targeted immunotherapies have not yet found their place in the clinic for HGSOC, the evidence above, as well as ongoing studies exploring the synergistic effects of PARPi with immune agents, including immune checkpoint inhibitors, suggests potential for targeting the immune response in HGSOC. Additionally, combining PARPi with epigenetic-modulating drugs may improve PARPi efficacy, by inducing a BRCA-defective phenotype to sensitise resistant cancer cells to PARPi. Finally, invigorating an immune response during PARPi therapy may engage anti-cancer immune responses that potentiate efficacy and mitigate the development of PARPi resistance. Here, we will review the emerging PARPi literature with a focus on PARPi effects on the immune response in HGSOC, as well as the potential of epigenetic combination therapies. We highlight the potential of transforming HGSOC from a lethal to a chronic disease and increasing the likelihood of cure.
There is great interest in developing efficient therapeutic cancer vaccines, as this type of therapy allows targeted killing of tumor cells as well as long-lasting immune protection. High levels of ...tumor-infiltrating CD8
T cells are associated with better prognosis in many cancers, and it is expected that new generation vaccines will induce effective production of these cells. Epigenetic mechanisms can promote changes in host immune responses, as well as mediate immune evasion by cancer cells. Here, we focus on epigenetic modifications involved in both vaccine-adjuvant-generated T cell immunity and cancer immune escape mechanisms. We propose that vaccine-adjuvant systems may be utilized to induce beneficial epigenetic modifications and discuss how epigenetic interventions could improve vaccine-based therapies. Additionally, we speculate on how, given the unique nature of individual epigenetic landscapes, epigenetic mapping of cancer progression and specific subsequent immune responses, could be harnessed to tailor therapeutic vaccines to each patient.
Stem cell differentiation depends on transcriptional activation driven by lineage‐specific regulators as well as changes in chromatin organization. However, the coordination of these events is poorly ...understood. Here, we show that T‐box proteins team up with chromatin modifying enzymes to drive the expression of the key lineage regulator, Eomes during endodermal differentiation of embryonic stem (ES) cells. The Eomes locus is maintained in a transcriptionally poised configuration in ES cells. During early differentiation steps, the ES cell factor Tbx3 associates with the histone demethylase Jmjd3 at the enhancer element of the Eomes locus to allow enhancer–promoter interactions. This spatial reorganization of the chromatin primes the cells to respond to Activin signalling, which promotes the binding of Jmjd3 and Eomes to its own bivalent promoter region to further stimulate Eomes expression in a positive feedback loop. In addition, Eomes activates a transcriptional network of core regulators of endodermal differentiation. Our results demonstrate that Jmjd3 sequentially associates with two T‐box factors, Tbx3 and Eomes to drive stem cell differentiation towards the definitive endoderm lineage.
Transcription factors Tbx3 and Eomes interact consecutively with the histone demethylase Jmjd3 to prompt chromatin dynamics required for embryonic stem cell differentiation towards definitive endoderm.
Cell-fate decisions and pluripotency are dependent on networks of key transcriptional regulators. Recent reports demonstrated additional functions of pluripotency-associated factors during early ...lineage commitment. The T-box transcription factor TBX3 has been implicated in regulating embryonic stem cell self-renewal and cardiogenesis. Here, we show that TBX3 is dynamically expressed during specification of the mesendoderm lineages in differentiating embryonic stem cells (ESCs) in vitro and in developing mouse and Xenopus embryos in vivo. Forced TBX3 expression in ESCs promotes mesendoderm specification by directly activating key lineage specification factors and indirectly by enhancing paracrine Nodal/Smad2 signaling. TBX3 loss-of-function analyses in the Xenopus underline its requirement for mesendoderm lineage commitment. Moreover, we uncovered a functional redundancy between TBX3 and Tbx2 during Xenopus gastrulation. Taken together, we define further facets of TBX3 actions and map TBX3 as an upstream regulator of the mesendoderm transcriptional program during gastrulation.
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