Heme oxygenase-1 (HO-1), a heme-degrading enzyme, is proven to have anti-apoptotic effects in several malignancies. In addition, HO-1 is reported to cause chemoresistance and increase cell survival. ...Growing evidence indicates that HO-1 contributes to the course of hematological malignancies as well. Here, the expression pattern, prognostic value, and the effect of HO-1 targeting in HMs are discussed.
According to the recent literature, it was discovered that HO-1 is overexpressed in myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), acute myeloblastic leukemia (AML), and acute lymphoblastic leukemia (ALL) cells and is associated with high-risk disease. Furthermore, in addition to HO-1 expression by leukemic and MDS cells, CML, AML, and ALL leukemic stem cells express this protein as well, making it a potential target for eliminating minimal residual disease (MRD). Moreover, it was concluded that HO-1 induces tumor progression and prevents apoptosis through various pathways.
HO-1 has great potential in determining the prognosis of leukemia and MDS patients. HO-1 induces resistance to several chemotherapeutic agents as well as tyrosine kinase inhibitors and following its inhibition, chemo-sensitivity increases. Moreover, the exact role of HO-1 in Chronic Lymphocytic Leukemia (CLL) is yet unknown. While findings illustrate that MDS and other leukemic patients could benefit from HO-1 targeting. Future studies can help broaden our knowledge regarding the role of HO-1 in MDS and leukemia. Video abstract.
Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have limited treatment options, particularly if they are transplantation or chimeric antigen receptor (CAR) T-cell ...ineligible, and novel therapeutics are needed. An 86-year-old woman with relapsed DLBCL received a novel, first-in-class small molecule inhibitor of N-myristoyltransferase (NMT) as the initial patient on a phase I dose escalation trial. Daily oral administration of 20 mg PCLX-001 tablets produced a pharmacokinetic profile suitable for single daily dosing: rapid oral absorption, followed by an apparent elimination half-life of 16 h, without systemic accumulation of drug by day 15. Pharmacodynamic tests showed no clear change in NMT1 and NMT2 levels or selected NMT substrate Lyn and HGAL protein levels in normal circulating blood mononuclear cells, suggesting a higher dose will be required for normal tissue toxicity. The patient did not experience any dose-limiting toxicities but had disease progression after 28 days of study therapy. Dose escalation continues in other patients in this first-in-human study of a new class of anticancer drug. We conclude that PCLX-001 oral monotherapy has suitable pharmacokinetic parameters for dose escalation, and that higher doses are required to achieve pharmacodynamic evidence of on-target activity in normal tissues. The current protocol is appropriately designed to achieve these ends, and the study proceeds without modification.
A growing body of evidence has revealed the role of innate immune cells in transplantation; however, the nature of natural killer cell involvement in rejection is still elusive. Here, we aimed to ...determine the impact of natural killer cell activities in acute and chronic renal transplant rejection.
This preliminary case-control study included 63 participants: 19 were patients with kidney allograft rejection (8 patients with acute rejection and 11 patients with chronic rejection) and 44 comprised the control group (22 patients who had well-functioning grafts posttransplant and 22 healthy subjects). In addition to natural killer cell frequency, we also measured intracellular interferon-? production and surface expression of CD107a as cytotoxic activity using flow cytometry.
We observed a significant increase in CD107a expression (P = .021) in patients with acute rejection versus those with well-functioning grafts. Moreover, production of interferon-? in patients with chronic rejection was significantly increased compared with patients with well-functioning grafts (P = .003). Finally, natural killer cell frequency was decreased in patients with rejection versus control groups; however, this reduction was not statistically significant.
These findings suggest that the increase in natural killer cell cytotoxicity is correlated with rejection in kidney transplant recipients and might be considered as a predictive marker in prevalence of graft rejection.
Myeloid-derived suppressor cells (MDSCs) are capable of suppressing the immune response. 5-Fluorouracil (5-FU) compared to other chemotherapy drugs have shown considerable decreases in the number of ...MDSCs without visible effects on T, B and natural killer cells, as well as dendritic cells (DCs). DC-based vaccines considered to be appropriate candidates for cancer immunotherapy. However, due to the presence of various factors like MDSCs in tumor microenvironment, DC vaccine cannot effectively perform its function. The purpose of this study was to evaluate the effect of low doses of 5-FU on the efficacy of DC-based vaccines in preventing and treating of melanoma tumor model. This research was performed on 28 melanoma tumor bearing C57BL/6 female mice. The mice were randomly divided to 4 groups, group 1 is control population while group 2 and 3 were treated with DC vaccine and 5-FU respectively and group 4 was treated with both DC Vaccine and 5-FU. The mice survival, tumor growth rate, number of MDSC and CD8+/ CD107a+ T cells in mice spleen were evaluated in each group with maximum result in group 4. Our results revealed that combination of DC vaccine and 5-FU reduced number of MDSCs (3%) and also tumor growth rate(10%)(p<0.05) and increased mice survival (70%) and increased CD8+ /CD107a+ T cells (25%). This study have shown that combinational therapy with DC vaccine improved immunity in tumor mice compared to the therapy consisting of DC vaccine or 5-FU only.
Background: It is supposed that human colorectal cancer consists of a phenotypically distinct population of tumorigenic cancer cells known as cancer stem cells (CSCs) which play a pivotal role in ...cancer progression, maintenance, metastasis, and the relapse. The aim of this effort was to investigate and compare biological characterizations of CD133 + with CD133− cell subsets isolated from both primary and metastatic human colorectal tumors. Materials and Methods: Using our optimized protocols, unfixed colorectal tumors were enzymatically and mechanically dissociated into single cells followed by evaluation of postdigestion viability. The obtained single cell suspensions were then subjected to cell sorting using magnetic beads according to CD133 marker. The resultant CD133 + and CD133− cell subsets were cultured in specific cell culture medium followed by aldehyde dehydrogenases (ALDH) activity assessment and flow cytometric analyses. Results: The results demonstrate that CD133 + cells have smaller size and lower complexity of intracellular structure, sphere formation ability, and ALDH enzyme activity while CD133− cells isolated from primary colon cancer samples were not able to form a sphere and did not show ALDH enzyme activity. Intriguingly, CD133− cells isolated from metastatic colorectal cancer specimen were able to form a sphere and shown ALDH enzyme activity. The present study indicates that our results are in agreement with SC theory and possibility of the existence of cellular plasticity among cancer subpopulations should be portrayed. Conclusion: We also conclude that this cellular plasticity is greatly affected by tumor microenvironment cues and the role of CSCs niche in cancer therapeutic strategies should be precisely considered.
Colorectal cancer (CRC) remains one of the most common and deadly cancers. Intestinal gut microflora is important to maintain and contributes to several intestinal functions, including the ...development of the mucosal immune system, absorption of complex macromolecules, synthesis of amino acids/vitamins and the protection against pathogenic microorganisms. It is well known that the gut microbiota changes or dysbiosis may have an essential impact in the initiation and promotion of chronic inflammatory pathways and also have a profound different genetic and epigenetic alterations leading to dysplasia, clonal expansion, and malignant transformation. Probiotic bacteria has antitumor activity with various mechanisms such as nonspecific physiological and immunological mechanisms. This review evaluates the effects of microbiota and probiotics in clinical trials, in vitro and animal model studies that have explored how probiotic against cancer development and also discusses the possible immunomodulatory mechanisms. Several mechanisms alteration of the intestinal microflora; inactivation of cancerogenic compounds; competition with putrefactive and pathogenic microbiota; improvement of the host's immune response; antiproliferative effects via regulation of apoptosis and cell differentiation; fermentation of undigested food; inhibition of tyrosine kinase; reduces the enteropathogenic complications before and after colon cancer surgery and improve diarrhea and it's have been able to create the integrity of gut mucosal and have stimulatory effects on the systemic immune system and prevent the CRC metastasis. Research in clinical trials encouraging findings that support a role of probiotics in CRC prevention and improve the safety and effectiveness of cancer therapy even though additional clinical research is still necessary.
Several mechanisms alteration of the intestinal microflora; inactivation of cancerogenic compounds; competition with putrefactive and pathogenic microbiota; improvement of the host's immune response; antiproliferative effects via regulation of apoptosis and cell differentiation; fermentation of undigested food; inhibition of tyrosine kinase; reduces the enteropathogenic complications before and after colon cancer surgery and improve diarrhea and it's; have been able to create the integrity of gut mucosal and have stimulatory effects on the systemic immune system and prevent the CRC metastasis.
Cervical cancer is as a kind of cancer beginning from the cervix. Given that cervical cancer could be observed in women who infected with papillomavirus, regular oral contraceptives, and multiple ...pregnancies. Early detection of cervical cancer is one of the most important aspects of the therapy of this malignancy. Despite several efforts, finding and developing new biomarkers for cervical cancer diagnosis are required. Among various prognostic, diagnostic, and therapeutic biomarkers, miRNA have been emerged as powerful biomarkers for detection, treatment, and monitoring of response to therapy in cervical cancer. Here, we summarized various miRNAs as an employable platform for prognostic, diagnostic, and therapeutic biomarkers in the treatment of cervical cancer.
Regulation of T cell function in the steady state is mediated by co-inhibitory receptors or immune checkpoints such as PD-1, CTLA-4, TIM-3 and LAG-3. Persistent antigen stimulation, during chronic ...viral infections and cancer, results in sustained expression of multiple co-inhibitory receptors and subsequently poor effector T cell function. Immune checkpoint blockade using monoclonal antibodies against PD-1, PDL-1 and CTLA-4 has been implemented as an immunotherapy strategy- resulting in restoration of T cell function and reduction of viral load or tumour growth. Immunomodulatory roles of commonly used cholesterol-lowering medications, atorvastatin and other statins, are widely documented. We have previously shown that atorvastatin can inhibit HIV-1 infection and replication. Here, for the very first time we discovered that atorvastatin also regulates activated T cell function by mediating downregulation of multiple co-inhibitory receptors, which corresponded with increased IL-2 production by stimulated T cells. In addition, we found that atorvastatin treatment reduces expression of mTOR and downstream T cell effector genes. We demonstrate a novel mechanism showing that atorvastatin inhibition of Ras-activated MAPK and PI3K-Akt pathways, and subsequent mTOR signalling promotes gross downregulation of co-inhibitory receptors. Thus, our results suggest that statins may hold particular promise in reinvigorating T cell function in chronic conditions.
The immunosuppressive state of the tumor microenvironment diminishes the efficacy of dendritic cell (DC)-based cancer immunotherapy. Inhibitory immune checkpoint molecules expressed on ...tumor-infiltrating T lymphocytes, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) molecules are one of the main barriers in priming T cells by DCs. Therefore, it seems that blockade of such molecules facilitates the T cells activation by the DC vaccine. In this study, we intended to suppress the expression of CTLA-4 molecule on tumor-infiltrating T cells by siRNA-loaded chitosan-lactate (CL) nanoparticles to facilitate priming anti- tumor T cells by tumor lysate-loaded DC vaccine. Nanoparticles (NPs) have also provided an opportunity for specific drug delivery into the tumor site. CL NPs exhibited favorable physicochemical characteristics (size about 75 nm, polydispersive index<0.2, and a zeta potential about 14), which were associated with a high transfection rate and low toxicity. Moreover, the administration of anti-CTLA-4 siRNA-loaded NPs into CT26 and 4 T1 tumor -bearing mice led to the downregulation of CTLA-4 on tumor -infiltrating T cells, which was associated with tumor regression and increased mice survival.
Moreover, while the treatment of tumor -bearing mice with DC vaccine had mild therapeutic outcomes, its combination with siRNA-loaded NPs may exhibit synergistic anti- tumor effects. This possible synergistic ameliorating effect is achieved through the reduction of immunosuppressive cells, the improved cytotoxicity of T lymphocytes, decreased inhibitory and increased inflammatory cytokines, and reduced angiogenesis and metastasis processes. These results indicate that the silencing of CTLA-4 can potentiate the T cell priming capacity of the DC vaccine, proposing a practical anti-cancer therapeutic approach.
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•In patients with cancer, Tregs are accumulated in tumors and the peripheral blood.•Tregs highly increased number has been regarded as the marker of poor prognosis in breast cancer.•Tregs ...manipulation like depletion can be novel approaches for treatment of breast cancer.
Despite marked advances in treatment approaches, breast cancer is still going to be more prevalent, worldwide. High levels of regulatory T (Treg) cells have repeatedly been demonstrated in circulation, lymph nodes, and tumor samples from patients with various cancer types. The transcription factor Forkhead box protein 3 (Foxp3)-expressing Treg cells have the high suppressive potential of the immune system and are fundamental in preserving immune homeostasis and self-tolerance. However, they enhance tumor development by curbing efficient anti-tumor immune mechanisms in malignancies. Moreover, the accumulation of Treg cells in breast tumors is related to the short overall survival of patients. Treg cell frequency has been applied as an independent predicting factor to diagnose patients with a high risk of relapse. Pulling out all populations of Treg cells to promote the efficacy of anticancer treatment methods may potentially lead to hazardous autoimmune disorders. Thus, realizing the exact structure of tumor-infiltrating Treg cells is pivotal to efficiently target Treg cells in tumors. There are exclusive and non-exclusive approaches to lower down and degrade the number/function of Treg cells. These approaches can include inhibiting tumoral migration, depletion, interference with function, and utilizing T cell plasticity. This review article attempts to clarify the implications concerning the involvement of Treg cells in breast cancer progression and discuss the current approaches in the treatment of this cancer via modulation of Treg cells function.
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