Search

Distant metastasis is a major cause of treatment failure in cancer patients and a key challenge to improving cancer care today. We hypothesized that enhancing anti-cancer immune response and inhibiting circulating tumor cells (CTCs) adhesion and transendothelial migration through synergistic multi-target approaches may effectively prevent cancer metastasis. “Fuyuan Decoction” (FYD) is a traditional Chinese medicine compound that is widely used to prevent postoperative metastasis in cancer patients, but its underlying mechanism remains unclear. In this work, we systematically elucidated the underlying molecular mechanism by which FYD prevents cancer metastasis through multi-compound and multi-target synergies in vitro and in vivo. FYD significantly prevented cancer metastasis at non-cytotoxic concentrations by suppressing the adhesion of CTCs to endothelial cells and their subsequent transendothelial migration, as well as enhancing anti-cancer immune response. Mechanistically, FYD interrupts adhesion of CTCs to vascular endothelium by inhibiting TNF-α-induced CAMs expression via regulation of the NF-κB signaling pathway in endothelial cells. FYD inhibits invasion and migration of CTCs by suppressing EMT, PI3K/AKT and FAK signaling pathways. Moreover, FYD enhances the anti-cancer immune response by significantly increasing the population of Tc and NK cells in the peripheral immune system. In addition, the chemical composition of FYD was determined by UPLC-HRMS, and the results indicated that multiple compounds in FYD prevents cancer metastasis through multi-target synergistic treatment. This study provides a modern medical basis for the application of FYD in the prevention of cancer metastasis, and suggesting that multi-drug and multi-target synergistic therapy may be one of the most effective ways to prevent cancer metastasis. [ABSTRACT FROM AUTHOR]

Individuals are exposed to intracellular pathogens (i.e. viruses and intracellular bacteria) and intestinal microbiota, collectively microorganisms (MOs), which enter the body during the host's lifetime. Altogether, MOs are a natural source of non-self antigens (MoAs) expressed by host's cells in the context of the HLA class I molecules, inducing a wide pool of specific memory CD8+ T cell clones. Such MoAs have been shown in selected cases to share sequence and structural homology with cellular self-antigens (molecular mimicry), possibly inducing autoimmune reactions leading to autoimmune diseases (ADs). We have recently shown that a molecular mimicry may be found also to selfantigens presented by cancer cells (i.e. tumor-associated antigens, TAAs). Consequently, memory CD8+ T cell clones specific for the MoAs may turn out to be a natural "anti-cancer vaccination" if a nascent tumor lesion should express TAAs similar or identical to MoAs. We postulate that selecting MoAs with high homology to TAAs would greatly improve the efficacy of cancer vaccines in both preventive and therapeutic settings. Indeed, non-self MoAs are potently immunogenic because not affected by central immune tolerance. Unravelling the impact of the antigenic molecular mimicry between MoAs and TAAs might pave the way for novel anti-cancer immunotherapies with unprecedented efficacy. [ABSTRACT FROM AUTHOR]

Individuals are exposed to intracellular pathogens (i.e. viruses and intracellular bacteria) and intestinal microbiota, collectively microorganisms (MOs), which enter the body during the host’s lifetime. Altogether, MOs are a natural source of non-self antigens (MoAs) expressed by host’s cells in the context of the HLA class I molecules, inducing a wide pool of specific memory CD8+ T cell clones. Such MoAs have been shown in selected cases to share sequence and structural homology with cellular self-antigens (molecular mimicry), possibly inducing autoimmune reactions leading to autoimmune diseases (ADs). We have recently shown that a molecular mimicry may be found also to self-antigens presented by cancer cells (i.e. tumor-associated antigens, TAAs). Consequently, memory CD8+ T cell clones specific for the MoAs may turn out to be a natural “anti-cancer vaccination” if a nascent tumor lesion should express TAAs similar or identical to MoAs. We postulate that selecting MoAs with high homology to TAAs would greatly improve the efficacy of cancer vaccines in both preventive and therapeutic settings. Indeed, non-self MoAs are potently immunogenic because not affected by central immune tolerance. Unravelling the impact of the antigenic molecular mimicry between MoAs and TAAs might pave the way for novel anti-cancer immunotherapies with unprecedented efficacy.

Distant metastasis is a major cause of treatment failure in cancer patients and a key challenge to improving cancer care today. We hypothesized that enhancing anti-cancer immune response and inhibiting circulating tumor cells (CTCs) adhesion and transendothelial migration through synergistic multi-target approaches may effectively prevent cancer metastasis. "Fuyuan Decoction" (FYD) is a traditional Chinese medicine compound that is widely used to prevent postoperative metastasis in cancer patients, but its underlying mechanism remains unclear. In this work, we systematically elucidated the underlying molecular mechanism by which FYD prevents cancer metastasis through multi-compound and multi-target synergies in vitro and in vivo . FYD significantly prevented cancer metastasis at non-cytotoxic concentrations by suppressing the adhesion of CTCs to endothelial cells and their subsequent transendothelial migration, as well as enhancing anti-cancer immune response. Mechanistically, FYD interrupts adhesion of CTCs to vascular endothelium by inhibiting TNF-α-induced CAMs expression via regulation of the NF-κB signaling pathway in endothelial cells. FYD inhibits invasion and migration of CTCs by suppressing EMT, PI3K/AKT and FAK signaling pathways. Moreover, FYD enhances the anti-cancer immune response by significantly increasing the population of Tc and NK cells in the peripheral immune system. In addition, the chemical composition of FYD was determined by UPLC-HRMS, and the results indicated that multiple compounds in FYD prevents cancer metastasis through multi-target synergistic treatment. This study provides a modern medical basis for the application of FYD in the prevention of cancer metastasis, and suggesting that multi-drug and multi-target synergistic therapy may be one of the most effective ways to prevent cancer metastasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ye, Lin, Zhou, Wang, Yao, Su, Qi, Zheng, Zhong, Chen, Huang and Lu.)

Accumulating evidence shows that the anti-cancer potential of the immune response that can be activated by modulation of the immunogenicity of dying cancer cells. This regulated cell death process is called immunogenic cell death (ICD) and constitutes a new innovating anti-cancer strategy with immune-modulatory potential thanks to the release of damage-associated molecular patterns (DAMPs). Some conventional clinically-used chemotherapeutic drugs, as well as preclinically-investigated compounds of natural origins such as anthracyclines, microtubule-destabilizing agents, cardiac glycosides or hypericin derivatives, possess such an immune-stimulatory function by triggering ICD. Here, we discuss the effects of ICD inducers on the release of DAMPs and the activation of corresponding signaling pathways triggering immune recognition. We will discuss potential strategies allowing to overcome resistance mechanisms associated with this treatment approach as well as co-treatment strategies to overcome the immunosuppressive microenvironment. We will highlight the potential role of metronomic immune modulation as well as targeted delivery of ICD-inducing compounds with nanoparticles or liposomal formulations to improving the immunogenicity of ICD inducers aiming at long-term clinical benefits. [ABSTRACT FROM AUTHOR]

Individuals are exposed to intracellular pathogens (i.e. viruses and intracellular bacteria) and intestinal microbiota, collectively microorganisms (MOs), which enter the body during the host's lifetime. Altogether, MOs are a natural source of non-self antigens (MoAs) expressed by host's cells in the context of the HLA class I molecules, inducing a wide pool of specific memory CD8 + T cell clones. Such MoAs have been shown in selected cases to share sequence and structural homology with cellular self-antigens (molecular mimicry), possibly inducing autoimmune reactions leading to autoimmune diseases (ADs). We have recently shown that a molecular mimicry may be found also to self-antigens presented by cancer cells (i.e. tumor-associated antigens, TAAs). Consequently, memory CD8 + T cell clones specific for the MoAs may turn out to be a natural "anti-cancer vaccination" if a nascent tumor lesion should express TAAs similar or identical to MoAs. We postulate that selecting MoAs with high homology to TAAs would greatly improve the efficacy of cancer vaccines in both preventive and therapeutic settings. Indeed, non-self MoAs are potently immunogenic because not affected by central immune tolerance. Unravelling the impact of the antigenic molecular mimicry between MoAs and TAAs might pave the way for novel anti-cancer immunotherapies with unprecedented efficacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tagliamonte and Buonaguro.)

Simple Summary: The growing interest in immunotherapy for the treatment of multiple myeloma demands a deep knowledge of the complex interactions between malignant and immune cells within the bone marrow. Indeed, understanding the cellular and molecular mechanisms underlying this network should represent the basis for the design of novel patient-oriented biological therapeutic approaches. Here, we describe the role of the main immune components of the myeloma niche along disease evolution and their implication in impairing/improving the response to anti-cancer treatments. Additionally, we provided an overview of the potential weakness of this pro-tumor interplay, evidencing novel therapeutic opportunities, which deserve future clinical investigations. Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by a multi-step evolutionary path, which starts with an early asymptomatic stage, defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease in 1% of cases per year, often through an intermediate phase known as "smoldering" MM (sMM). Interestingly, while many genomic alterations (translocation, deletions, mutations) are usually found at early stages, they are not sufficient (alone) to determine disease evolution. The latter, indeed, relies on significant "epigenetic" alterations of different normal cell populations within the bone marrow (BM) niche, including the "evasion" from immune-system control. Additionally, MM cells could "educate" the BM immune microenvironment (BM-IM) towards a pro-inflammatory and immunosuppressive phenotype, which ultimately leads to disease evolution, drug resistance, and patients' worse outcome. Indeed, it is not a case that the most important drugs for the treatment of MM include immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide) and monoclonal antibodies (daratumumab, isatuximab, and elotuzumab). On these bases, in this review, we describe the most recent advances in the comprehension of the role of the different cells composing the BM-IM, and we discuss the potential molecular targets, which could represent new opportunities to improve current treatment strategies for MM patients. [ABSTRACT FROM AUTHOR]

B7-H3 belongs to the B7 family of immune checkpoint proteins, which are important regulators of the adaptive immune response and emerging key players in human cancer. B7-H3 is a transmembrane protein expressed on the surface of tumor cells, antigen presenting cells, natural killer cells, tumor endothelial cells, but can also be present in intra- and extracellular vesicles. Additionally, B7-H3 may be present as a circulating soluble isoform in serum and other body fluids. B7-H3 is overexpressed in a variety of tumor types, in correlation with poor prognosis. B7-H3 is a promising new immunotherapy target for anti-cancer immune response, as well as a potential biomarker. Besides its immunoregulatory role, B7-H3 has intrinsic pro-tumorigenic activities related to enhanced cell proliferation, migration, invasion, angiogenesis, metastatic capacity and anti-cancer drug resistance. B7-H3 has also been found to regulate key metabolic enzymes, promoting the high glycolytic capacity of cancer cells. B7-H3 receptors are still not identified, and little is known about the molecular mechanisms underlying B7-H3 functions. Here, we review the current knowledge on the involvement of B7-H3 in human cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)