Programmed cell death ligand‐1: A dynamic immune checkpoint in cancer therapy

Antibody‐based immunotherapies play a pivotal role in cancer research with efficient achievements in tumor suppression. Tumor survival is assisted by modulation of immune checkpoints to create imbalances between immune cells and cancer cell's environment. The modulation results in T‐cell signal inhibition ultimately inert its proliferation and activation against various tumor cells. PD‐L1, a 40 kDa transmembrane protein of B7 family, binds with PD‐1 on the membrane of T cells which results in inhibition of T‐cell proliferation and activation. PD‐L1/PD‐1 pathway has generated novel target sites for antibodies that can block PD‐L1/PD‐1 interactions. The blockage results in T‐cell proliferation and tumor cell suppression. The PD‐L1 immune checkpoint strategies’ development, expression and regulations, signal inhibitions, and developmental stages of PD‐L1/PD‐1 antibodies are briefly discussed here in this review. All this information will provide a base for new therapeutic development against PD‐L1 and PD‐1 immune checkpoint interactions and will make available promising treatment options.     

Optimizing Patient Outcomes with PD-1/PD-L1 Immune Checkpoint Inhibitors for the First-Line Treatment of Advanced Non–Small Cell Lung Cancer

The rapidly expanding repertoire of immune checkpoint inhibitors (ICIs) now includes two agents, pembrolizumab and atezolizumab, approved for first-line treatment of advanced non–small cell lung cancer (aNSCLC) as monotherapy or as part of chemoimmunotherapy. This review summarizes the clinical evidence supporting these indications, with a focus on strategies to optimize patient outcomes. These strategies include patient and tumor factors, adverse-effect profiles, pharmacokinetic and pharmacodynamic drug interactions, and quality of life and cost-effectiveness considerations. We performed a systematic literature search of the PubMed, Scopus, and Google Scholar databases, as well as a search of the conference proceedings of the American Society of Clinical Oncology, European Society for Medical Oncology, and American Association for Cancer Research (through August 31, 2019). The addition of ICIs to conventional chemotherapy as first-line treatment against aNSCLC is now part of the standard of care options. However, even though ICIs may be cost-effective in patients with aNSCLC, high drug and other associated costs can still be a barrier to treatment for patients. Moreover, the adverse-effect profiles of ICIs differ significantly from conventional chemotherapy, and some immune-related adverse effects may have a lasting impact on quality of life. Therefore, in adhering to a patient-centered model of care, clinicians should be mindful of patient- and treatment-specific factors when considering therapeutic options for patients with aNSCLC. Although the role of the immune system in cancer progression and regression has not been fully elucidated, the full clinical potential of immunotherapeutics in the treatment of cancer likely remains to be unleashed.     

Radioimmunoimaging and targeting treatment in an immunocompetent murine model of triple‐negative breast cancer using radiolabeled anti–programmed death‐ligand 1 monoclonal antibody

The overall aim of this study was to evaluate whether iodine‐131 radiolabeled monoclonal antibody (mAb) targeting programmed death‐ligand 1 (PD‐L1) can be used for imaging of PD‐L1 expression noninvasively in vivo and playing synergistic effect combined with immunotherapy. Anti‐PD‐L1 mAb was radiolabeled with iodine‐131 (¹³¹I‐PD‐L1 mAb) and was characterized in vitro. Biodistribution and imaging in vivo were performed periodically. Therapy study was conducted in triple‐negative breast cancer–bearing BALB/c mice. As results, the labeling efficiencies of ¹³¹I‐PD‐L1 mAb reached 80% ± 3%, with radiochemical purity of 97% ± 1%. ¹³¹I‐PD‐L1 mAb preserved the capacity to bind living PD‐L1‐expressing cells specifically in vitro. Tumor radioactivity uptake of ¹³¹I‐PD‐L1 mAb was significantly higher than that of control groups. The xenografts were clearly imaged from 48 to 72 hours noninvasively after injection of ¹³¹I‐PD‐L1 mAb, while the xenografts were not imaged in control groups. Tumor growth was significantly inhibited, and median survival time was remarkably prolonged in combination therapy group compared with control groups. It was concluded that ¹³¹I‐PD‐L1 mAb can be a potential theranostic candidate for visualizing of PD‐L1 expression noninvasively and performing synergistic therapy in carcinomas.     

Targeting the PD-1 pathway: a new hope for gastrointestinal cancers

Background: VEGF, HER2 and EGFR targeted agents are currently used in gastric, esophageal and colorectal cancers. However, treatment outcomes are still poor in most gastrointestinal (GI) cancers. Immune checkpoints are one of the most promising immunotherapy approaches. In this review article, we aim to discuss the efficacy and safety of anti-PD-1/PD-L1 therapies in GI cancers, including gastric, esophageal and colorectal cancer in published or reported recent studies.

Scope: A literature search was made from PubMed and ASCO Annual Meeting abstracts by using the following search keywords: “nivolumab”, “pembrolizumab”, “avelumab”, “GI cancers” “anti-PD1 therapy” and “anti-PD-L1 therapy”. The last search was on 2 November 2016. The most important limitation of our review is that most of the data on anti-PD-1/PD-L1 therapies in GI cancers relies on phase 1 and 2 trials.

Findings: Currently, there are two anti-PD-1 (nivolumab and pembrolizumab) and one anti-PDL1 (atezolizumab) agents approved by FDA. After the treatment efficacy of immune checkpoint blockade was shown in melanoma, renal cell cancer and non-squamous lung cancer, trials which evaluate immune checkpoint blockade in GI cancers are ongoing. Early results of trials have been promising and encouraging for patients with advanced stage gastroesophageal cancer. According to early results of published trials, response to anti-PD1/PD-L1 agents appears to be associated with tumor PD-L1 levels. According to two recently published phase 2 trials, the clinical benefits of immune checkpoint blockade with both nivolumab and pembrolizumab were limited in patients with microsatellite instability (MSI) positive advanced colorectal cancer. However, several phase 2/3 trials are still ongoing.

Conclusion: Both pembrolizumab and nivolumab show promising efficacy with acceptable safety data in published trials in GI cancers, especially in refractory MSI positive metastatic colorectal cancer.     

Undo the brake of tumour immune tolerance with antibodies,peptide mimetics and small molecule compounds targeting PD‐1/PD‐L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells

Recent clinical success of immunotherapy that inhibits the negative immune regulatory pathway programmed cell death protein‐1/PD‐1 ligand 1 (PD‐1/PD‐L1) has initiated a new era in the treatment of metastatic cancer. However, greater challenges remain to treat all cancers. The molecular architecture in the immune synapse constituting positive engagements for immune activation and negative checkpoints against immune hyperactivity is regulated dynamically by interaction between proteostasis and tumour microenvironment. This article reviews recent progresses in our understandings of the cellular and molecular mechanisms of the negative checkpoint PD‐1/PD‐L1 behaviours in immune tolerance of tumourigenesis and metastasis. We provide an overview on PD‐L1 gene expression regulation, protein turnover, intra‐ and extracellular trafficking, exosome‐mediated inter‐cellular transport, molecular interface peptide mimetics, inhibitory chemical compounds such as metformin, and antibody dynamics. We summarise PD‐L1 post‐translational modifications including glycosylation, palmitoylation, phosphorylation and ubiquitination, reflecting future research directions and opportunities in identifying tumour‐specific signalling targets, their regulatory molecules and pathways for intervention into various types of cancers.     

Analyzing the percentage of different PD‐1+ T cell subsets in peripheral blood and bronchoalveolar lavage fluid of small cell lung cancer patients: A prospective study

The present study was designed to evaluate the percentage of different programmed cell death‐1 (PD‐1)⁺ T cell subsets in peripheral blood and bronchoalveolar lavage fluid (BALF) of small cell lung cancer (SCLC) patients. The percentages of PD‐1⁺ T cell subsets in peripheral blood and BALF samples obtained from 52 lung cancer and 20 pneumonia patients, and 20 healthy controls were examined by flow cytometry. In addition, clinical parameters, such as erythrocyte sedimentation rate (ESR) and C‐reactive protein (CRP) levels, were also determined using Spearman's correlation test to assess their association with PD‐1⁺ T cell subsets. These present results revealed that the percentage of circulating PD‐1⁺ Tfh and peripheral helper T cells (Tph) cells significantly increased in peripheral blood of SCLC patients, when compared to non‐small cell lung cancer (NSCLC) pneumonia patients and healthy controls. In addition, PD‐1⁺ Tfh cells were also significantly enhanced in patients in the extensive‐stage group. In contrast, the BALF samples of SCLC patients exhibited a significant decrease in percentage of Tph cells. An overall imbalance was observed between PD‐1⁺Tfh and Tph cells in both compartments. Furthermore, SCLC patients exhibited a significant decrease in the percentage of circulating PD‐1⁺ Tfh and Tph cells following chemotherapy, and the in vitro analysis revealed that the concentration of IL‐2 and IFN‐γ derived from PD‐1 + Tfh cells in SCLC were significantly lower than that from NSCLC. However, this had no significant correlation with disease severity. The present study indicated that elevated circulating PD‐1⁺ T cells can primarily be used as a biomarker for disease diagnosis and a potential therapeutic target.     

Low KISS1 expression predicts poor prognosis for patients with colorectal cancer: A meta‐analysis

KISS1 and KISS1R, a novel pair of metastasis suppressors, are likely to be associated with the prognosis of colorectal cancer (CRC). Here, a meta‐analysis was performed to study the role of KISS1 and KISS1R in CRC. Heterogeneity, stability and publication bias were all estimated. Six publications describing a total of 559 CRC patients were included in the present study. Low KISS1 expression predicted 70% higher risk of poor prognosis for general patients (HR, 1.71; 95% CI, 1.28–2.29) and 99% higher risk for East Asian patients (HR, 1.99; 95% CI, 1.46–2.72). Limited evidence indicated that decreased KISS1R expression might predict poor outcome (HR, 2.96; 95% CI, 1.51–5.82). Neither heterogeneity nor publication bias was identified. The current analyses suggest that low KISS1 expression predicts poor overall survival among East Asian patients with CRC. Evidence on other races and KISS1R are still insufficient, and additional studies are required to clarify the risk of CRC associated with KISS1R by race.     

Inhibitors of slit protein interactions with the heparan sulphate proteoglycan glypican‐1: Potential agents for the treatment of spinal cord injury

1. The heparan sulphate proteoglycan glypican‐1 is a major high‐affinity ligand of the Slit proteins. 2. Messenger RNA for both Slit‐2 and glypican‐1 is strongly upregulated and coexpressed in the reactive astrocytes of injured adult brain, suggesting a possible function of Slit proteins and glypican‐1 in the adult central nervous system as significant components of the inhibitory environment that prevents axonal regeneration after injury. 3. Based on the hypothesis that adverse effects on axonal regeneration may be due to a glypican–Slit complex or the retention of glypican‐binding C‐terminal proteolytic processing fragments of Slit at the injury site, we used ELISA to examine a number of small molecules and low molecular weight heparin analogues for their ability to inhibit glypican–Slit interactions. 4. Our studies have led to the identification of several potent inhibitors with a favourable therapeutic profile that can now be tested in a spinal cord injury model. Among the most promising of these are a low molecular weight heparin produced by periodate oxidation and having no significant anticoagulant activity, the chemically sulphonated yeast‐derived phosphomannan PI‐88 and a number of randomly derivatized water‐soluble sulphated dextrans.     

Drug resistance and cancer stem cells: the shared but distinct roles of hypoxia‐inducible factors HIF1α and HIF2α

Chemotherapy resistance is a major contributor to poor treatment responses and tumour relapse, the development of which has been strongly linked to the action of cancer stem cells (CSCs). Mounting evidence suggests that CSCs are reliant on low oxygen conditions and hypoxia‐inducible factors 1α and 2α (HIF1α and HIF2α) to maintain their stem cell features. Research in the last decade has begun to clarify the functional differences between the two HIFα subtypes (HIFαs). Here, we review and discuss these differences in relation to CSC‐associated drug resistance. Both HIFαs contribute to CSC survival but play different roles –HIF1α being more responsible for survival functions and HIF2α for stemness traits such as self‐renewal – and are sensitive to different degrees of hypoxia. Failure to account for physiologically relevant oxygen concentrations in many studies may influence the current understanding of the roles of HIFαs. We also discuss how hypoxia and HIFαs contribute to CSC drug resistance via promotion of ABC drug transporters Breast cancer resistance protein (BCRP), MDR1, and MRP1 and through maintenance of quiescence. Additionally, we explore the PI3K/AKT cell survival pathway that may support refractory cancer by promoting CSCs and activating both HIF1α and HIF2α. Accordingly, HIF1α and HIF2α inhibition, potentially via PI3K/AKT inhibitors, could reduce chemotherapy resistance and prevent cancer relapse.     

Predictive effect of PD-L1 expression for immune checkpoint inhibitor (PD-1/PD-L1 inhibitors) treatment for non-small cell lung cancer: A meta-analysis

BackgroundProgrammed death-ligand-1 (PD-L1) is a well-known predictive biomarker in non-small cell lung cancer (NSCLC) patients, however, its accuracy remains controversial. Here, we investigated the correlation between PD-L1 expression level and efficacy of its inhibitors, and hence assessed the predictive effect of PD-L1 expression.MethodsStudies that evaluated the efficacy of programmed death-1 (PD-1)/ PD-L1 inhibitors in advanced NSCLC patients according to tumor PD-L1 expression levels were searched for on Medline, Cochrane Library, and Embase. The pooled risk ratio (RR) and 95% confidence intervals (95% CIs) were calculated for the objective response rate (ORR) with overall survival (OS) and progression-free survival (PFS) were measured in terms of hazard ratio (HR) and the corresponding 95% CIs.Results1432 NSCLC patients from six randomized controlled trials (RCTs) were included and three PD-1/PD-L1 inhibitors (atezolizumab, nivolumab, and pembrolizumab) were used to treat the patients. A significantly higher ORR was observed in the high PD-L1 expression group compared to the low expression group (0.35 [95% CI, 0.30–0.40] vs 0.11 [95% CI, 0.09–0.14]). The results of the subgroup analysis, grouped by the type of drugs and antibodies which assess immune checkpoint inhibitors were identical with the pooled result. However, our study showed that PD-L1 expression was neither prognostic nor predictive of overall survival (OS) or progression-free survival (PFS) in patients treated with PD-1/PD-L1 inhibitors compared to chemotherapy.ConclusionsPD-L1 can be a predictive biomarker for ORR. Nevertheless, PD-L1 expression is not a good predictive tool for OS and PFS.     

Evaluation of 124I-JS001 for hPD1 immuno-PET imaging using sarcoma cell homografts in humanized mice

JS001 (toripalimab) is a humanized IgG monoclonal antibody which strongly inhibits programmed cell death protein 1 (PD1). In this study, we used a different iodine isotype (^nat/124/125I) to label JS001 probes to target the human PD1 (hPD1) antigen. In vitro, the half maximal effective concentration (EC₅₀) value of ^natI-JS001 did not significantly differ from that of JS001. The uptake of ¹²⁵I-JS001 by activated T cells was 5.63 times higher than that by nonactivated T cells after 2 h of incubation. The binding affinity of ¹²⁵I-JS001 to T cells of different lineages after phytohemagglutinin (PHA) stimulation reached 4.26 nmol/L. Humanized PD1 C57BL/6 mice bearing mouse sarcoma S180 cell tumors were validated for immuno-positron emission tomography (immuno-PET) imaging. Pathological staining was used to assess the expression of PD1 in tumor tissues. The homologous ¹²⁴I-human IgG (¹²⁴I-hIgG) group or blocking group was used as a control group. Immuno-PET imaging showed that the uptake in the tumor area of the ¹²⁴I-JS001 group at different time points was significantly higher than that of the blocking group or the ¹²⁴I-hIgG group in the humanized PD1 mouse model. Taken together, these results suggest that this radiotracer has potential for noninvasive monitoring and directing tumor-specific personalized immunotherapy in PD1-positive tumors.     

Tubeimoside-1 induces TFEB-dependent lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting mTOR

Programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) cascade is an effective therapeutic target for immune checkpoint blockade (ICB) therapy. Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity. Using flow cytometry-based assay, we identify tubeimoside-1 (TBM-1) as a promising antitumor immune modulator that negatively regulates PD-L1 level. TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1. Furthermore, TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma (LLC) and B16 melanoma tumor xenograft via activating tumor-infiltrating T-cell immunity. Mechanistically, TBM-1 triggers PD-L1 lysosomal degradation in a TFEB-dependent, autophagy-independent pathway. TBM-1 selectively binds to the mammalian target of rapamycin (mTOR) kinase and suppresses the activation of mTORC1, leading to the nuclear translocation of TFEB and lysosome biogenesis. Moreover, the combination of TBM-1 and anti-CTLA-4 effectively enhances antitumor T-cell immunity and reduces immunosuppressive infiltration of myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells. Our findings reveal a previously unrecognized antitumor mechanism of TBM-1 and represent an alternative ICB therapeutic strategy to enhance the efficacy of cancer immunotherapy.     

Applying artificial intelligence for cancer immunotherapy

Artificial intelligence (AI) is a general term that refers to the use of a machine to imitate intelligent behavior for performing complex tasks with minimal human intervention, such as machine learning; this technology is revolutionizing and reshaping medicine. AI has considerable potential to perfect health-care systems in areas such as diagnostics, risk analysis, health information administration, lifestyle supervision, and virtual health assistance. In terms of immunotherapy, AI has been applied to the prediction of immunotherapy responses based on immune signatures, medical imaging and histological analysis. These features could also be highly useful in the management of cancer immunotherapy given their ever-increasing performance in improving diagnostic accuracy, optimizing treatment planning, predicting outcomes of care and reducing human resource costs. In this review, we present the details of AI and the current progression and state of the art in employing AI for cancer immunotherapy. Furthermore, we discuss the challenges, opportunities and corresponding strategies in applying the technology for widespread clinical deployment. Finally, we summarize the impact of AI on cancer immunotherapy and provide our perspectives about underlying applications of AI in the future.     

Alterations of DNA damage response pathway: Biomarker and therapeutic strategy for cancer immunotherapy

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP–AMP synthase-stimulator of interferon genes (cGAS–STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.     

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.     

Pure drug nano-assemblies: A facile carrier-free nanoplatform for efficient cancer therapy

Nanoparticulate drug delivery systems (Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity. Recently, pure drug nano-assemblies (PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even 100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.