Targeting autophagy in colorectal cancer: An update on pharmacological small-molecule compounds

Autophagy, an evolutionarily highly conserved cellular degradation process, plays the Janus role (either cytoprotective or death-promoting) in colorectal cancer, so the targeting of several key autophagic pathways with small-molecule compounds may be a new therapeutic strategy. In this review, we discuss autophagy-associated cell death pathways and key cytoprotective autophagy pathways in colorectal cancer. Moreover, we summarize a series of small-molecule compounds that have the potential to modulate autophagy-associated cell death or cytoprotective autophagy for therapeutic purposes. Taken together, these findings demonstrate the Janus role of autophagy in colorectal cancer, and shed new light on the exploitation of a growing number of small-molecule compounds to target autophagy in future cancer drug discovery.     

BICC1 as a novel prognostic biomarker in gastric cancer correlating with immune infiltrates

AimBicC family RNA-binding protein 1 (BICC1) codes an RNA-binding protein that regulates gene expression and modulates cell proliferation and apoptosis. We aim at investigating the role of BICC1 in gastric carcinogenesis.MethodsBICC1 mRNA expression in gastric cancer (GC) was examined using the Tumor Immune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Correlations between BICC1 expression and clinicopathological parameters were analyzed. The Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier plotter databases were used to examine the clinical prognostic significance of BICC1 in GC. Signaling pathways related to BICC1 expression were identified by gene set enrichment analysis (GSEA).TIMER and CIBERSORT were used to analyze the correlations among BICC1, BICC1-coexpressed genes and tumor-infiltrating immune cells.ResultsBICC1 was highly expressed in GC and significantly correlated with grade (P = 0.002), TNM stage (P = 0.033), invasion depth (P = 0.001) and vital status (P = 0.009) of GC patients. High BICC1 expression correlated with poor overall survival. The GSEA results showed that cell adhesion-, tumor- and immune- related pathways were significantly enriched in samples with high BICC1 expression. BICC1 and its coexpressed genes were positively related to tumor-infiltrating immune cells and were strongly correlated with tumor-infiltrating macrophages (all r ≥ 0.582, P < 0.0001). The CIBERSORT database revealed that BICC1 correlated with M2 macrophages (P < 0.0001), regulatory T cells (P < 0.0001), resting mast cells (P < 0.0001), activated memory CD4+ T cells (P = 0.002), resting NK cells (P = 0.002), activated dendritic cells (P = 0.002), and follicular helper T cells (P = 0.016). The results from TIMER database confirmed that BICC1 is closely associated with the markers of M2 macrophages and tumor-associated macrophages (all r ≥ 0.5, P < 0.0001).ConclusionBICC1 may be a potential prognostic biomarker in GC and correlates with immune infiltrates.     

Recent advances in developing polymeric micelles for treating cancer: Breakthroughs and bottlenecks in their clinical translation

Polymeric micelles (PMs) have been explored pre-clinically for the delivery of chemotherapeutics to treat cancer. Their unique features, such as easy surface functionalization, stimuli-responsiveness, good stability, ability to modify drug release, enhanced permeation and retention effect, and potential to encapsulate more than one type of therapeutic molecules at a time, make them unique carriers for the targeted delivery or for enhancing the bioavailability of chemotherapeutics. PMs can also be used as theranostic nanocarriers for the mapping of drug therapy along with tumor imaging in patients with cancer. This review focuses on the limitations of existing treatment strategies and on innovative approaches employed for the functionalization of PMs for targeting cancer cells. In addition, the bottlenecks associated with the translation of PMs from the laboratory to clinics are also discussed.     

Factors affecting tumor responders and predictive biomarkers of toxicities in cancer patients treated with immune checkpoint inhibitors

Cancer immunotherapy has brought a great revolution in the treatment of advanced human cancer. Immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) have been widely administrated in the past years and demonstrated promising in a variety of malignancies. While some patients show benefit from ICIs, others do not respond or even develop resistance to these therapies. Among the responders, the treatments are consequently accompanied with immune-related adverse effects (irAEs), which are diverse in their effected organs, degree of severity and timing. Some of the toxicities are fatal and result in discontinuance of immunotherapy. The toxicity profile from anti-CTLA-4 to anti-PD-1/PD-L1 immunotherapies is distinct from those caused by conventional anticancer therapies, though their presentation may be similar. In order to better help clinicians recognize, monitor and manage irAEs in a growing population of cancer patients who are receiving ICI therapy, this article summarizes the FDA approved ICIs and focuses on (1) existing toxic evidence related to ICIs, (2) occurrence of irAEs, (3) factors influencing tumor responders treated with ICIs, (4) predictive biomarkers of irAEs, and (5) new potential mechanisms of resistance to ICI therapy.     

Mitochondrial-targeted nanoparticles: Delivery and therapeutic agents in cancer

Antitumor agents are delivered via nanoparticles (NPs) to the mitochondria. The drugs attack the mitochondria resulting in mitochondrial damage and the release of cytochrome C (Cyto-C). Cyto-C binds with Apaf1 and Caspase-9 to form an apoptosome. The apoptosome activates Caspase 3, which ultimately results in the death of cancer cells.

1. Download : Download high-res image (143KB)
2. Download : Download full-size image

     

Functional modulation of CD8+ T cell by approved novel immune enhancer: Nocardia rubra Cell-Wall Skeletons (Nr-CWS)

Nocardia rubra cell wall skeleton (Nr-CWS) has been reported to have innate immunostimulating and anti-tumor activities. However, the immunomodulatory effects of Nr-CWS on CD8+ T cells and their related mechanisms are still unknown. In this work, our team purified CD8⁺T cells from spleen cells and explored the phenotype and function of NR-CWS in vitro on CD8⁺T cells. We observed that Nr-CWS can significantly up-regulate the expression of CD69 and CD25 on CD8⁺T cells, with no significant effect on apoptosis or cell death of CD8⁺T cells that occurs in vitro during culture. In addition, the effect of perforin and granzyme B was increased after Nr-CWS treatment, but did not substantially alter the expression of TRAIL and FasL. A variety of cytokine analyses have shown that of the cytokines examined (IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-6 and IL-10), only IFN-γ and TNF The increase in -α was more pronounced, and the effect of Nr-CWS in CD8⁺T cell culture medium on CD8+ T cells was independent of Th cells. Our results demonstrated that Nr-CWS could up-regulate CD69 and CD25 expression on CD8⁺T cells, promoting IFN-γ and TNF-α secretion, and enhancing perforin and granzyme B production. Thus Nr-CWS may have Immunoaugmenting therapeutic activity via an increase in CD8⁺T cells response.     

Berberine diminishes cancer cell PD-L1 expression and facilitates antitumor immunity via inhibiting the deubiquitination activity of CSN5

Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has become a major pillar of cancer immunotherapy. Compared with antibodies targeting, small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed. Here we identified berberine (BBR), a proven anti-inflammation drug, as a negative regulator of PD-L1 from a set of traditional Chinese medicine (TCM) chemical monomers. BBR enhanced the sensitivity of tumour cells to co-cultured T-cells by decreasing the level of PD-L1 in cancer cells. In addition, BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). BBR triggered PD-L1 degradation through ubiquitin (Ub)/proteasome-dependent pathway. Remarkably, BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5 (CSN5) and inhibited PD-1/PD-L1 axis through its deubiquitination activity, resulting in ubiquitination and degradation of PD-L1. Our data reveals a previously unrecognized antitumor mechanism of BBR, suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.     

Adipokines as targets in musculoskeletal immune and inflammatory diseases

Adipokines are the principal mediators in adipose signaling. Nevertheless, besides their role in energy storage, these molecules can be produced by other cells, such as immune cells or chondrocytes. Given their pleiotropic effects, research over the past few years has also focused on musculoskeletal diseases, showing that these adipokines might have relevant roles in worsening the disease or improving the treatment response. In this review, we summarize recent advances in our understanding of adipokines and their role in the most prevalent musculoskeletal immune and inflammatory disorders.     

A cyclodextrin-based nanoformulation achieves co-delivery of ginsenoside Rg3 and quercetin for chemo-immunotherapy in colorectal cancer

The immune checkpoint blockade therapy has profoundly revolutionized the field of cancer immunotherapy. However, despite great promise for a variety of cancers, the efficacy of immune checkpoint inhibitors is still low in colorectal cancer (CRC). This is mainly due to the immunosuppressive feature of the tumor microenvironment (TME). Emerging evidence reveals that certain chemotherapeutic drugs induce immunogenic cell death (ICD), demonstrating great potential for remodeling the immunosuppressive TME. In this study, the potential of ginsenoside Rg3 (Rg3) as an ICD inducer against CRC cells was confirmed using in vitro and in vivo experimental approaches. The ICD efficacy of Rg3 could be significantly enhanced by quercetin (QTN) that elicited reactive oxygen species (ROS). To ameliorate in vivo delivery barriers associated with chemotherapeutic drugs, a folate (FA)-targeted polyethylene glycol (PEG)-modified amphiphilic cyclodextrin nanoparticle (NP) was developed for co-encapsulation of Rg3 and QTN. The resultant nanoformulation (CD-PEG-FA.Rg3.QTN) significantly prolonged blood circulation and enhanced tumor targeting in an orthotopic CRC mouse model, resulting in the conversion of immunosuppressive TME. Furthermore, the CD-PEG-FA.Rg3.QTN achieved significantly longer survival of animals in combination with Anti-PD-L1. The study provides a promising strategy for the treatment of CRC.     

Duocarmycin-based antibody–drug conjugates as an emerging biotherapeutic entity for targeted cancer therapy: Pharmaceutical strategy and clinical progress

Duocarmycins are a class of DNA minor-groove-binding alkylating molecules. For the past decade, various duocarmycin analogues have been used as payloads in the development of antibody–drug conjugates (ADCs). Currently, more than 15 duocarmycin-based ADCs have been studied preclinically, and some of them such as SYD985 have been granted Fast-Track Designation status. Nevertheless, progress in duocarmycin-based ADCs also faces challenges, with setbacks including the termination of BMS-936561/MDX-1203. In this review, we discuss issues associated with the efficacy, pharmacokinetic profile, and toxicological activity of these biotherapeutics. Furthermore, we summarize the latest advances in duocarmycin-based ADCs that have different target specificities and linker chemistries. Evidence from preclinical and clinical studies has indicated that duocarmycin-based ADCs are promising biotherapeutics for oncological application in the future.     

Isolation and purification of immune cells from the liver

Isolating and purifying liver immune cells are crucial for observing the changes in intrahepatic immune responses during the development of liver diseases and exploring the potential immunological mechanisms. Therefore, the aim of this study was to provide an optimal protocol for isolating immune cells with a high yield and less damage. We compared mechanical dissection and collagenase digestion, and the results were represented by the proportion of lymphocytes, Kupffer cells and neutrophils. The apoptosis rates of liver immune cells resulted by different isolation protocols were compared by Annexin V-staining using flow cytometric analysis. Our data indicated that the enzymatic digestion in vitro was more efficient than the mechanical dissection in vitro with a suitable collagenase IV concentration of 0.01%, and the purification of liver immune cells by a one-step density gradient centrifugation in 33% Percoll had the definite advantage of a higher proportion of the target cells. We also provided evidence that enzymatic digestion in vitro method was superior to collagenase digestion in situ for liver T lymphocytes, NK cells and NKT cells isolation and purification. This protocol was also validated in human liver samples. In conclusion, we developed an optimal protocol for isolating and purifying immune cells from mouse and human liver samples in vitro by 0.01% collagenase IV and 33% Percoll density gradient centrifugation with the advantages of higher cell yields and viability. This method provides a basis for further studying liver immune cells and liver immunity with a wide range of applications.     

Roles of TGF-β signaling pathway in tumor microenvirionment and cancer therapy

Transforming growth factor β (TGF- β) signaling pathway has pleiotropic effects on cell proliferation, differentiation, adhesion, senescence, and apoptosis. TGF-β can be widely produced by various immune or non-immune cells and regulate cell behaviors through autocrine and paracrine. It plays essential roles in biological processes including embryological development, immune response, and tumor progression. Few cell signalings can contribute to so many pleiotropic functions as the TGF- β signaling pathway in mammals. The significant function of TGF-β signaling in tumor progression and evasion leading it to draw great attention in scientific and clinical research. Understanding the mechanism of TGF- β signaling provides us with chances to potentiate the effectiveness and selectivity of this therapeutic method. Herein, we review the molecular and cellular mechanisms of TGF-β signaling in carcinomas and tumor microenvironment. Then, we enumerate main achievements of TGF-β blockades used or being evaluated in cancer therapy, providing us opportunities to improve therapeutical approaches in the tumor which thrive in a TGF-β-rich environment.     

An immune risk score with potential implications in prognosis and immunotherapy of metastatic melanoma

Melanoma is a highly aggressive cancer with a poor prognosis. We found that immune response played important roles in melanoma metastasis by GSEA analysis. Therefore, we constructed the immune risk score (IRS) by the LASSO-COX analysis in the sequencing metastatic samples from the TCGA database. Then, initial diagnosis patients with metastasis were selected as the test cohort. Importantly, we adopted overall survival (OS) as the survival outcome for initial diagnosis patients, while adopting the observed survival interval (OBS) as the survival outcome for sequencing samples which could avoid biologically meaningless associations. We found that the IRS had high power for predicting 2, 3 and 5-year survival in training (AUC = 0.70, 0.69 and 0.68) and test cohorts (AUC = 0.72, 0.70 and 0.65). The IRS was significantly associated with prognosis both in the metastatic samples (HR = 1.60, 95% CI = 1.16–2.19) and patients with metastasis (HR = 2.89, 95% CI = 1.69–4.53). we further used other independent melanoma cohorts from the GEO databases to confirm the reliability and validity of the IRS (P < 0.01 in all cohorts). The practical nomogram was also built using the IRS and clinical information with high c-index both in training (0.76, 95%CI = 0.72–0.80) and test cohorts (0.72, 95%CI = 0.65–0.79). Finally, IRS showed the predictive value of survival outcome and response of immunotherapy patients, and increased the predictive ability of current immune checkpoint gene markers. In conclusion, the IRS can serve as a potential biomarker for prognosis and responsiveness to immune checkpoint blockade immunotherapy in metastatic melanoma patients.     

The role of extracellular ATP in homeostatic immune cell migration

Antigen stimulation induces adenosine triphosphate (ATP) release from naïve lymphocytes in lymphoid tissues. However, previous studies indicated that the non-lytic release of ATP also occurs in most tissues and cell types under physiological conditions. Here, we show that extracellular ATP (eATP) is indeed constitutively produced by naïve T cells in response to lymphoid chemokines in uninflamed lymph nodes and is involved in the regulation of immune cell migration. In this review, we briefly summarize the homeostatic role of extracellular ATP in immune cell migration in vivo.     

Pharmacological inhibition of GSK3 promotes TNFα-induced GM-CSF via up-regulation of ERK signaling in nasopharyngeal carcinoma (NPC)

Granulocyte-macrophage colony stimulating factor (GM-CSF) functions to drive nasopharyngeal cancer (NPC) metastasis via recruitment and activation of macrophages. However, the source and the regulation of GM-CSF in tumor microenvironment of NPC are not fully understood. In this study, we found that TNFα induced GM-CSF production in NPC CNE1, CNE2, and 5-8F cells in time- and dose-dependent manners. GM-CSF production was tolerant, because the pre-treatment of NPC cells with TNFα down-regulated the GM-CSF production induced by TNFα re-treatment. TNFα activated glycogen synthase kinase-3 (GSK-3), which is an enzyme to regulate glycogen synthesis, and also is a critical downstream element of the PI3K/Akt to regulate cell survival. GSK3 inhibitors up-regulated TNFα-induced GM-CSF, and reversed GM-CSF tolerance induced by TNFα pre-treatment, suggesting that GSK3 activation down-regulated GM-CSF production. GM-CSF down-regulation was not related to ubiquitin-editing enzyme A20. The over-expression of A20 did not regulate GM-CSF production induced by TNFα. However, GSK3 inhibitors up-regulated ERK activation, which contributed to the production of GM-CSF induced by TNFα, suggesting that GSK3 negatively regulated TNFα-induced GM-CSF via down-regulation of ERK signaling. Taking together, these results suggested that GSK3 pathway may be a target for the regulation of TNFα-induced GM-CSF in the tumor microenvironment.