The molecular biology and therapeutic potential of Nrf2 in leukemia

NF-E2-related factor 2 (Nrf2) transcription factor has contradictory roles in cancer, which can act as a tumor suppressor or a proto-oncogene in different cell conditions (depending on the cell type and the conditions of the cell environment). Nrf2 pathway regulates several cellular processes, including signaling, energy metabolism, autophagy, inflammation, redox homeostasis, and antioxidant regulation. As a result, it plays a crucial role in cell survival. Conversely, Nrf2 protects cancerous cells from apoptosis and increases proliferation, angiogenesis, and metastasis. It promotes resistance to chemotherapy and radiotherapy in various solid tumors and hematological malignancies, so we want to elucidate the role of Nrf2 in cancer and the positive point of its targeting. Also, in the past few years, many studies have shown that Nrf2 protects cancer cells, especially leukemic cells, from the effects of chemotherapeutic drugs. The present paper summarizes these studies to scrutinize whether targeting Nrf2 combined with chemotherapy would be a therapeutic approach for leukemia treatment. Also, we discussed how Nrf2 and NF-κB work together to control the cellular redox pathway. The role of these two factors in inflammation (antagonistic) and leukemia (synergistic) is also summarized

Natural killer cell-derived exosomes for cancer immunotherapy: innovative therapeutics art

Abstract Chimeric antigen receptor natural killer cells (CAR-NK) promote off-the-shelf cellular therapy for solid tumors and malignancy.However,, the development of CAR-NK is due to their immune surveillance uncertainty and cytotoxicity challenge was restricted. Natural killer cell-derived exosome (NK-Exo) combine crucial targeted cellular therapies of NK cell therapies with unique non-toxic Exo as a self-origin shuttle against cancer immunotherapy. This review study covers cytokines, adoptive (autologous and allogenic) NK immunotherapy, stimulatory and regulatory functions, and cell-free derivatives from NK cells. The future path of NK-Exo cytotoxicity and anti-tumor activity with considering non-caspase-independent/dependent apoptosis and Fas/FasL pathway in cancer immunotherapy. Finally, the significance and implication of NK-Exo therapeutics through combination therapy and the development of emerging approaches for the purification and delivery NK-Exo to severe immune and tumor cells and tissues were discussed in detail

T-cell immunoglobulin and ITIM domain, as a potential immune checkpoint target for immunotherapy of colorectal cancer

The importance of the tumor microenvironment in cancer progression has been well studied for many years. Immune checkpoint inhibitors (ICIs) are regarded as potential strategies in enhancing the immune responses in patients with cancer, particularly colorectal cancer (CRC). Notably, CRCs are extraordinarily heterogeneous and mostly are microsatellite-stable (MSS) or cold tumors, which means that the immune response is not usually as strong as that of foreign cells. T-cell immunoglobulin and ITIM domain (TIGIT) is a new immune checkpoint receptor overexpressed inside the CRC tumor-immune microenvironments. Moreover, several studies have shown that TIGIT in combination with other ICIs and/or conventional treatments, can lead to a robust anti-tumor response in CRC. This review looks deep inside TIGIT expression patterns, their various functions, and possible immunotherapy strategies to increase survival rates and decrease immune-related adverse events

The role of SF3B1 and NOTCH1 in the pathogenesis of leukemia

The discovery of new genes/pathways improves our knowledge of cancer pathogenesis and presents novel potential therapeutic options. For instance, splicing factor 3b subunit 1 (SF3B1) and NOTCH1 genetic alterations have been identified at a high frequency in hematological malignancies, such as leukemia, and may be related to the prognosis of involved patients because they change the nature of malignancies in different ways like mediating therapeutic resistance; therefore, studying these gene/pathways is essential. This review aims to discuss SF3B1 and NOTCH1 roles in the pathogenesis of various types of leukemia and the therapeutic potential of targeting these genes or their mutations to provide a foundation for leukemia treatment

The role of Th17 cells in the pathogenesis and treatment of breast cancer

Breast cancer is a severe problem worldwide due to an increase in mortality and prevalence among women. Despite early diagnostic procedures as well as advanced therapies, more investigation is required to find new treatment targets. Various factors and mechanisms, such as inflammatory conditions, can play a crucial role in cancer progression. Among them, Th17 cells are identified as effective CD4(+) T cells that play an essential role in autoimmune diseases and inflammation which may be associated with anti-tumor responses. In addition, Th17 cells are one of the main factors involved in cancer, especially breast cancer via the inflammatory process. In tumor immunity, the exact mechanism of Th17 cells is not entirely understood and seems to have a dual function in tumor development. Various studies have reported that cytokines secreted by Th17 cells are in close relation to cancer stem cells and tumor microenvironment. Therefore, they play a critical role in the growth, proliferation, and invasion of tumor cells. On the other hand, most studies have reported that T cells suppress the growth of tumor cells by the induction of immune responses. In patients with breast cancer compared to normal individuals, various studies have been reported that the Th17 population dramatically increases in peripheral blood which results in cancer progression. It seems that Th17 cells by creating inflammatory conditions through the secretion of cytokines, including IL-22, IL-17, TNF-α, IL-21, and IL-6, can significantly enhance breast cancer progression. Therefore, to identify the mechanisms and factors involved in the activation and development of Th17 cells, they can provide an essential role in preventing breast cancer progression. In the present review, the role of Th17 cells in breast cancer progression and its therapeutic potential was investigated

Prostaglandin E2 as a potent therapeutic target for treatment of colon cancer

Although colon cancer is one of the most important triggers of cancer related mortality, a few therapeutic options exist for this disease, including combination chemotherapy, anti-EGFR and anti-angiogenic agents. However, none of these therapeutics are fully effective for complete remission, and this issue needs further investigations, particularly in the patients with advanced disease. It has been shown that colon carcinogenesis process is associated with upregulation of prostaglandin (PG) levels. Moreover, conversion of pre-malignant cells to malignant was also related with increased generation of PGs in susceptible subjects. Among the prostanoids, PGE2 is the most important produced member which generated in high levels by colon tumor cells. Generation of PGE2 by action of cyclooxygenase (COX)-2 can promote growth and development, resistance to apoptosis, proliferation, invasion and metastasis, angiogenesis and drug resistance in colon cancer. Increased levels of PGE2 and COX-2 in colon cancer is reported by various investigators which was associated with disease progression. It is suggested that there is a positive feedback loop between COX-2 and PGE2, in which function of COX-2 induces generation of PGE2, and upregulation of PGE2 increases the expression of COX-2 in colon cancer. Although an existence of this feedback loop is well-documented, its precise mechanism, signaling pathways, and the particular E-type prostanoid (EP) receptor mediating this feedback are elusive. Therefore, it seems that targeting COX-2/PGE2/EP receptors may be supposed as a potent therapeutic strategy for treatment of colon cancer. In this review, we try to clarify the role of PGE2 in cancer progression and its targeting for treatment of colon cancer

Dual Blockade of PD-1 and LAG3 Immune Checkpoints Increases Dendritic Cell Vaccine Mediated T Cell Responses in Breast Cancer Model

Purpose Increasing the efficiency of unsuccessful immunotherapy methods is one of the most important research fields. Therefore, the use of combination therapy is considered as one of the ways to increase the effectiveness of the dendritic cell (DC) vaccine. In this study, the inhibition of immune checkpoint receptors such as LAG3 and PD-1 on T cells was investigated to increase the efficiency of T cells in response to the DC vaccine. Methods We used trimethyl chitosan-dextran sulfate-lactate (TMC-DS-L) nanoparticles (NPs) loaded with siRNA molecules to quench the PD-1 and LAG3 checkpoints’ expression. Results Appropriate physicochemical characteristics of the generated NPs led to efficient inhibition of LAG3 and PD-1 on T cells, which was associated with increased survival and activity of T cells, ex vivo. Also, treating mice with established breast tumors (4T1) using NPs loaded with siRNA molecules in combination with DC vaccine pulsed with tumor lysate significantly inhibited tumor growth and increased survival in mice. These ameliorative effects were associated with increased anti-tumor T cell responses and downregulation of immunosuppressive cells in the tumor microenvironment and spleen. Conclusion These findings strongly suggest that TMC-DS-L NPs loaded with siRNA could act as a novel tool in inhibiting the expression of immune checkpoints in the tumor microenvironment. Also, combination therapy based on inhibition of PD-1 and LAG3 in combination with DC vaccine is an effective method in treating cancer that needs to be further studied

Different T cell related immunological profiles in COVID‐19 patients compared to healthy controls

In various pathological conditions, cellular immunity plays an important role in immune responses. Among immune cells, T lymphocytes pdomote cellular and humoral responses as well as innate immunity. Therefore, careful investigation of these cells has a significant impact on accurate knowledge in COVID-19 disease pathogenesis. In current research, the frequency and function of various T lymphocytes involved in immune responses examined in SARS‐CoV-2 patients with various disease severity compared to normal subjects. In order to make an accurate comparison among patients with various disease severity, this study was performed on asymptomatic recovered cases (n = 20), ICU hospitalized patients (n = 30), non-ICU hospitalized patients (n = 30), and normal subjects (n = 20). To precisely evaluate T cells activity following purification, their cytokine secretion activity was examined. Similarly, immediately after purification of Treg cells, their inhibitory activity on T cells was investigated. The results showed that COVID-19 patients with severe disease (ICU hospitalized patients) not only had a remarkable increase in Th1 and Th17 but also a considerable decrease in Th2 and Treg cells. More importantly, as the IL-17 and IFN-γ secretion was sharply increased in severe disease, the secretion of IL-10 and IL-4 was decreased. Furthermore, the inhibitory activity of Treg cells was reduced in severe disease patients in comparison to other groups. In severe COVID-19 disease, current findings indicate when the inflammatory arm of cellular immunity is significantly increased, a considerable reduction in anti-inflammatory and regulatory arm occurred