Biological effects of IL-15 on immune cells and its potential for the treatment of cancer.

Interleukin-15 (IL-15) has recently emerged as a novel immunomodulatory cytokine in cancer immunotherapy. IL-15 has the potential to reject and destroy cancer cells in the tumor microenvironment by expanding and activating natural killer (NK), natural killer T (NKT), and memory (m) CD8+T cells. Due to the feasible outcomes obtained from preclinical studies and phase 1/2 clinical trials, IL-15-based therapy, including chimeric antigen receptor (CAR) T cell or CAR NK cell infusion following in vitro expansion in the presence of IL-15, used in combination with checkpoint inhibitors and other therapy may extend to clinical practice in the future. It is also important to understand the biological characteristics of IL-15 to ensure the maximal benefit of therapeutic strategies. Here, we summarize the current development of IL-15 in the following areas: anti-tumor mechanisms in the tumor microenvironment, advances in IL-15-based therapy itself or in combination with other methods, including biological agents, monoclonal antibodies, and adoptive immunotherapy.

Preclinical and clinical studies into the bioactivity of low-dose naltrexone (LDN) for oncotherapy.

Naltrexone (NTX) is a nonspecific opioid antagonist that exerts pharmacological effects on the opioid axis by blocking opioid receptors distributed in cytoplastic and nuclear regions. NTX has been used in opioid use disorder (OUD), immune-associated diseases, alcoholism, obesity, and chronic pain for decades. However, low-dose naltrexone (LDN) also exhibits remarkable inhibition of DNA synthesis, viability, and other functions in numerous cancers and is involved in immune remodeling against tumor invasion and chemical toxicity. The potential anticancer activity of LDN is a focus of basic research. Herein, we summarize the associated studies on LDN oncotherapy to highlight the potential mechanisms and prospective clinical applications.

Low-dose naltrexone plays antineoplastic role in cervical cancer progression through suppressing PI3K/AKT/mTOR pathway.

The incidence of cervical cancer is increasing annually worldwide. Low-dose naltrexone (LDN) has been reported to delay tumor progression, but the mechanism remains unclear. Here, we found that low-dose naltrexone could upregulate the expression of OGFr. Additionally, LDN could suppress the abilities of colony formation, migration and invasion in cervical cancer cells. LDN could also inhibit cervical cancer progression in mice model. Moreover, LDN indirectly reduced the expressions of PI3K, pAKT and mTOR in vitro and in vivo. Therefore, LDN may be considered a potential treatment option for cervical cancer.

Methionine enkephalin (MENK) suppresses lung cancer by regulating the Bcl-2/Bax/caspase-3 signaling pathway and enhancing natural killer cell-driven tumor immunity.

The aim of this study was to investigate how methionine enkephalin (MENK) regulates the biological behavior of lung cancer cells and to further explore its anti-lung cancer mechanisms in vitro and in vivo. The results showed that MENK enhanced the expression of opioid receptor (OGFr) and induced apoptosis of lung cancer cells by activating the Bcl-1/Bax/caspase-3 signaling pathway in vitro and in vivo. However, the regulatory effects of MENK disappeared after blockade of the OGFr. This confirmed that a prerequisite for the anti-tumor action of MENK is binding to OGFr. Additionally, we observed that MENK treatment enhanced the immunogenicity of lung cancer by enhancing the exposure of calreticulin and high mobility group box 1, and increasing the expression of NKG2D ligands. Further studies showed that MENK treatment increased the expression of natural killer (NK) cell-related cytokines such as granzyme B and interferon-γ and NK cell activation. Thus, we concluded that MENK might inhibit the proliferation of lung cancer cells by activating the Bcl-2/Bax/caspase-3 signaling pathway and enhancing immunogenicity and NK cell-driven tumor immunity.

Research progress of opioid growth factor in immune-related diseases and cancer diseases.

Methionine enkephalin (MENK) has an important role in both neuroendocrine and immune systems. MENK was known as an opioid growth factor (OGF) for its growth regulatory characteristics. OGF interacts with the OGF receptor (OGFr) to inhibit DNA synthesis by upregulating p16 and/or p21, which delays the cell cycle transition from G0/G1 to S phase, and inhibits cell proliferation. In addition, OGF combines with OGFr in immune cells to exert its immunomodulatory activity and regulate immune function. OGF has been studied as an immunomodulator in a variety of autoimmune diseases, including multiple sclerosis, inflammatory bowel disease, diabetes and viral infections, and has been proven to relieve symptoms of certain diseases in animal and in vitro experiments. Also, OGF and OGFr have various anti-tumor molecular mechanisms. OGF can be used as the primary therapy alone or combined with other drugs to treat tumors. This article summarizes the research progress of OGF in immune-related diseases and cancer diseases.

A novel mechanism of lung cancer inhibition by methionine enkephalin through remodeling the immune status of the tumor microenvironment.

This study examined the antitumor effect of methionine enkephalin (MENK) against lung cancer in vivo and in vitro and explored the underlying mechanisms. Changes in the immune status of the tumor microenvironment (TME) in response to MENK administration were examined in mice. MENK significantly inhibited the proliferation of lung cancer cells in vivo and in vitro by regulating the Wnt/ß-catenin pathway and causing cell cycle arrest at the G0/G1 phase. Knockdown of opioid growth factor receptor abolished the effect of MENK on lung cancer cells. The immune status of the TME of mice differed between the MENK and control groups. MENK increased the infiltration of M1-type macrophages, natural killer cells, CD8+ T cells, CD4+ T cells, and dendritic cells into the TME, and decreased the proportion of myeloid inhibitory cells and M2-type macrophages. Immunohistochemical analysis of the expression of cytokines in the TME showed that MENK upregulated IL-15, IL-21, IFN-γ, and granzyme B and downregulated IL-10 and TGF-ß1 in mice. Taken together, these finding indicate that MENK may be a potential agent for lung cancer treatment in the future, especially for overcoming immune escape and immune resistance.

Methionine enkephalin activates autophagy and stimulates tumour cell immunogenicity in human cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (CSCC) is a common skin tumour. Due to weak immunogenicity, recurrence is frequent after treatment. In this study, we explored the effects and mechanisms of methionine enkephalin (MENK), an endogenous opioid peptide and negative growth regulator, in CSCC. MENK inhibited A431 cell proliferation and promoted apoptosis through the opioid growth factor receptor (OGFr). Importantly, MENK also induced autophagy in CSCC and stimulated the emission of DAMPs in A431 cells, which resulted in enhanced activation of dendritic cells (DC).In conclusion, MENK provides an effective method with therapeutic potential to modulate the CSCC microenvironment by utilizing autophagy in the cancer cells.

Regulatory role of methionine enkephalin in myeloid-derived suppressor cells and macrophages in human cutaneous squamous cell carcinoma.

The antitumor effects of methionine enkephalin (MENK), also known as opioid growth factor (OGF), including its inhibitory effects on cutaneous squamous cell carcinoma (CSCC), have been established. In this study, we determined the precise mechanism by which MENK suppresses CSCC cell growth. In particular, MENK induced G0/G1 cell cycle arrest and promoted apoptosis in CSCC cells via the Bcl-2/Bax/Caspase-3 signaling pathway. Moreover, MENK reduced immunosuppression by downregulating the number of myeloid-derived suppressor cells (MDSCs) and regulating the polarization of tumor-associated macrophages from M2 to M1 in vivo. Furthermore, JAK2/STAT3, an important tumor-promotion and immunosuppression signaling pathway that is involved in MDSC expansion in tumors and macrophage polarization, was inhibited. These findings highlight the potential of the JAK2/STAT3 signaling pathway as a therapeutic target and suggest the clinical application of MENK for CSCC.

Iron in the NEEM ice core relative to Asian loess records over the last glacial-interglacial cycle.

Mineral dust can indirectly affect the climate by supplying bioavailable iron (Fe) to the ocean. Here, we present the records of dissolved Fe (DFe) and total Fe (TDFe) in North Greenland Eemian Ice Drilling (NEEM) ice core over the past 110 kyr BP. The Fe records are significantly negatively correlated with the carbon-dioxide (CO2) concentrations during cold periods. The results suggest that the changes in Fe fluxes over the past 110 kyr BP in the NEEM ice core are consistent with those in Chinese loess records because the mineral-dust distribution is controlled by the East Asian deserts. Furthermore, the variations in the dust input on a global scale are most likely driven by changes in solar radiation during the last glacial-interglacial cycle in response to Earth's orbital cycles. In the last glacial-interglacial cycle, the DFe/TDFe ratios were higher during the warm periods (following the post-Industrial Revolution and during the Holocene and last interglacial period) than during the main cold period (i.e. the last glacial maximum (LGM)), indicating that the aeolian input of iron and the iron fertilization effect on the oceans have a non-linear relationship during different periods. Although the burning of biomass aerosols has released large amounts of DFe since the Industrial Revolution, no significant responses are observed in the DFe and TDFe variations during this period, indicating that severe anthropogenic contamination has no significant effect on the DFe (TDFe) release in the NEEM ice core.

A case study using 2019 pre-monsoon snow and stream chemistry in the Khumbu region, Nepal.

This case study provides a framework for future monitoring and evidence for human source pollution in the Khumbu region, Nepal. We analyzed the chemical composition (major ions, major/trace elements, black carbon, and stable water isotopes) of pre-monsoon stream water (4300-5250 m) and snow (5200-6665 m) samples collected from Mt. Everest, Mt. Lobuche, and the Imja Valley during the 2019 pre-monsoon season, in addition to a shallow ice core recovered from the Khumbu Glacier (5300 m). In agreement with previous work, pre-monsoon aerosol deposition is dominated by dust originating from western sources and less frequently by transport from southerly air mass sources as demonstrated by evidence of one of the strongest recorded pre-monsoon events emanating from the Bay of Bengal, Cyclone Fani. Elevated concentrations of human-sourced metals (e.g., Pb, Bi, As) are found in surface snow and stream chemistry collected in the Khumbu region. As the most comprehensive case study of environmental chemistry in the Khumbu region, this research offers sufficient evidence for increased monitoring in this watershed and surrounding areas.

The iron records and its sources during 1990-2017 from the Lambert Glacial Basin shallow ice core, East Antarctica.

In this study, a shallow ice core (12.5 m, called LGB) was drilled at the Lambert Glacial Basin, East Antarctica. The major ion and metal elements were measured at 5-6 cm resolution in this shallow core, which covered the period 1990-2017. Therefore, an annual-resolution record of iron (Fe) concentrations and fluxes were reconstructed in this shallow ice core. Although the Fe data is comparable to previous results, our results emphasized that much more dissolved Fe (DFe) from the Cerro Hudson volcanic event (August 1991) was transported to the East Antarctic ice sheet, in comparison with the Pinatubo volcanic event (June 1991). The aeolian dust may be the primary DFe source during 1990-2017. In particular, the DFe variations may be affected by the biomass burning emissions in two periods (1990-1998 and 2014-2017). While total dissolved Fe (TDFe) variations were controlled by the climatic conditions since 2000 because of the temperature (δ18O) decreasing at East Antarctica. These Fe data will be useful to assess the modern bioavailable Fe release for the Antarctica ice sheet.

Fe variation characteristics and sources in snow samples along a traverse from Zhongshan Station to Dome A, East Antarctica.

Iron concentrations in the Southern Ocean are thought to act as a driver of the regular glacial-interglacial cycles in atmospheric carbon dioxide (CO2). This study presents the concentrations of bioavailable Fe (dissolved Fe (DFe) and total dissolved Fe (TDFe)), major ions (Na+, K+, Mg2+, Ca2+, Cl-,NO3-,SO42- and methanesulfonic acid (MSA)), heavy metal elements (Sr, Pb, V, Ti and Cd), and rare earth elements (REEs; specifically, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu) and the oxygen and hydrogen isotopic compositions (δ18O and δD) from a series of surface snow samples collected during from January 22 to February 5, 2017 along a traverse from Zhongshan Station to Dome A in East Antarctica. The results reflect the Antarctic surface snow Fe and the other trace element concentrations on the East Antarctica ice sheet. In particular, the DFe and TDFe concentrations were measured using inductively coupled plasma sector field mass spectrometry (SF-ICP-MS). The concentration patterns of DFe and TDFe show three different stages along this transect. First, there is an abrupt decrease with distance inland from the coast and then a slight decreasing trend with increasing elevation. The maximum concentrations were observed at distances of 450-600 km from the coast, indicating that there are different potential sources and/or transporting air masses. The variations show that the sources and processes that deliver bioavailable Fe differ along this transect. These data are useful for assessing bioavailable Fe release from the Antarctic ice sheet.