PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity. Antibody blockade of PD-L1 can activate an anti-tumor immune response leading to ...durable remissions in a subset of cancer patients. Here, we describe an alternative mechanism of PD-L1 activity involving its secretion in tumor-derived exosomes. Removal of exosomal PD-L1 inhibits tumor growth, even in models resistant to anti-PD-L1 antibodies. Exosomal PD-L1 from the tumor suppresses T cell activation in the draining lymph node. Systemically introduced exosomal PD-L1 rescues growth of tumors unable to secrete their own. Exposure to exosomal PD-L1-deficient tumor cells suppresses growth of wild-type tumor cells injected at a distant site, simultaneously or months later. Anti-PD-L1 antibodies work additively, not redundantly, with exosomal PD-L1 blockade to suppress tumor growth. Together, these findings show that exosomal PD-L1 represents an unexplored therapeutic target, which could overcome resistance to current antibody approaches.
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•Genetic blockade of exosomal PD-L1 extends survival by promoting anti-tumor immunity•Exosomal PD-L1 suppresses T cell activity in the draining lymph node•Exosome-deficient tumor cells induce systemic anti-tumor immunity and memory•Exosomal PD-L1 appears to be resistant to anti-PD-L1 antibody blockade
Exosomal PD-L1 systemically acts to suppress the anti-tumor immune response, and its genetic blockage promotes T cell activity in the draining lymph node to induce systemic anti-tumor immunity and memory.
To evaluate the emerging role of immunomodulatory antibodies in cancer treatment. Antibodies (ipilimumab and tremelimumab) targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), an inhibitory molecule ...on T cells, represent the vanguard of these new drugs.
We performed a systematic review of the clinical studies examining the clinical activity of anti-CTLA-4 antibodies. We also review the potential mechanisms and toxicities associated with these treatments.
Clinical activity with anti-CTLA-4 monoclonal antibodies (mAbs) has paved the way for additional T-cell immunomodulatory monoclonal antibody (mAb) approaches for the treatment of cancer to be investigated. Because anti-CTLA-4 mAbs target the immune system and not the tumor, they may provide significant potential advantages over traditional antitumor mAbs, chemotherapies, and immunotherapies (ie, vaccines and cytokines). Other antibodies, such as CD137 agonists, CD40 agonists, and PD-1 antagonists, are currently in various stages of preclinical and clinical development.
Available clinical data suggest that anti-CTLA-4 mAbs are very different from traditional mAbs, chemotherapies, and immunotherapies in terms of patterns of response, duration of response, and adverse event profile. Ongoing clinical studies aim to establish the efficacy and safety of anti-CTLA-4 mAbs as monotherapy or in combination with other drugs for the treatment of metastatic melanoma and a variety of other cancer types.
Risk perception has been an important construct in understanding tourists’ trip planning. Surprisingly, while tourists’ perceived tourist–host identity risk (THIR) plays an essential role in this ...process, its effects have been overlooked. Against this backdrop, this study develops a THIR scale and investigates how it shapes the intention of mainland Chinese tourists to revisit Hong Kong, and also investigates the spread of positive word-of-mouth (WoM) by conducting multiple online surveys with mainlanders. The results show that THIR is a uni-dimensional construct which is robustly measured by 12 items. It undermines revisit intention and the spread of positive WoM because of lower emotional solidarity followed by anticipation of unpleasant experience. This negative serial mediation is weaker for people who have a strong Chinese identity and perceive high THIR of an alternative destination (Macao). Meaningful implications are provided for destination marketers.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and confers a poor prognosis. Beyond standard systemic therapy with multikinase inhibitors, recent studies ...demonstrate the potential for robust and durable responses from immune checkpoint inhibition in subsets of HCC patients across disease etiologies. The majority of HCC arises in the context of chronic inflammation and from within a fibrotic liver, with many cases associated with hepatitis virus infections, toxins, and fatty liver disease. Many patients also have concomitant cirrhosis which is associated with both local and systemic immune deficiency. Furthermore, the liver is an immunologic organ in itself, which may enhance or suppress the immune response to cancer arising within it. Here, we explore the immunobiology of the liver from its native state to chronic inflammation, fibrosis, cirrhosis and then to cancer, and summarize how this unique microenvironment may affect the response to immunotherapy.
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Knowledge of circulating immune cell types and states associated with SLE remains incomplete. We profiled more than 1.2 ...million peripheral blood mononuclear cells (162 cases, 99 controls) with multiplexed single-cell RNA sequencing (mux-seq). Cases exhibited elevated expression of type 1 interferon-stimulated genes (ISGs) in monocytes, reduction of naïve CD4
T cells that correlated with monocyte ISG expression, and expansion of repertoire-restricted cytotoxic
CD8
T cells. Cell type-specific expression features predicted case-control status and stratified patients into two molecular subtypes. We integrated dense genotyping data to map cell type-specific cis-expression quantitative trait loci and to link SLE-associated variants to cell type-specific expression. These results demonstrate mux-seq as a systematic approach to characterize cellular composition, identify transcriptional signatures, and annotate genetic variants associated with SLE.
Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here, we ...reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency on the histone H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8+ and CD4+ effector T cells that eliminate tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity.
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•EZH2 expression is elevated in tumor-infiltrating (TI) Tregs•Pharmacological inhibition of EZH2 destabilizes FOXP3 expression and slows tumor growth•Genetic disruption of Ezh2 function in Tregs leads to robust anti-tumor immunity•Blockade of EZH2 in Tregs reprograms TI-Tregs to gain pro-inflammatory activity
EZH2 plays an intrinsic role in neoplastic cells as an oncogene, prompting the development of EZH2 inhibitors for cancer therapy. Wang et al. show that disrupting EZH2 function also has immunomodulatory activities and, when blocked in Tregs, promotes potent cancer immunity.
Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an ...immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling
. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti-PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8
T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. SIGNIFICANCE: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti-PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.
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Although prostate cancer was not historically considered to be a particularly immune-responsive cancer, recent clinical trials have demonstrated that immunotherapy for prostate cancer can lead to ...improvements in overall survival (OS). These studies include randomized controlled trials with sipuleucel-T and another with PROSTVAC-VF, both of which rely on stimulating the immune system to target prostate proteins. This review discusses the most promising developments over the past year in immune-based therapy for prostate cancer and the opportunities that lie ahead. Recent randomized immunotherapy trials in prostate cancer have demonstrated improvements in OS but without the concomitant improvements in progression-free survival. This uncoupling of survival from clinical response poses challenges to clinical management, because conventional measures of objective response cannot be used to identify patients benefiting from treatment. There is a significant need to identify immunologic or clinical surrogates for survival so that clinical benefit can be assessed in a timely manner. Immunotherapy is now an established treatment approach for prostate cancer, with multiple clinical trials demonstrating improvements in OS. Significant challenges to this modality remain, including determining best clinical setting for immunotherapy, identifying patients who benefit, and defining relevant clinical and immunologic end points. Nevertheless, the broader availability of novel immunotherapies will provide opportunities not only to target different components of the immune system but also to combine immunotherapies with other treatments for improved clinical efficacy.
Theme park operators need to understand their competitiveness in a destination to increase their market share. This study adopted the big data approach by analysing online reviews to assess the ...competitiveness of a theme park called Ocean Park (HKOP) against its competitor Disneyland (HKDL) in Hong Kong. Firstly, the strengths and weaknesses of HKOP were identified through importance performance analysis (IPA) and asymmetric impact performance analysis (AIPA). Results revealed that urgent action is required for the ‘Staff’, ‘Fast pass’, and ‘F&B and prices’ attributes, since they are the basic attributes that perform poorly. Secondly, to determine HKOP's competitive position against its rival HKDL, importance performance competitor analysis (IPCA) and asymmetric impact competitor analysis (AICA) were performed. On the one hand, the IPCA results indicated that the ‘Shows’, ‘Spend time’, and ‘Time & weather’ attributes are the strengths of HKOP when compared with HKDL. On the other hand, the AICA findings suggested urgent action for the ‘Child friendly’, ‘Waiting time’, ‘F&B and prices’, ‘Staff’, and ‘Accessibility’ attributes of HKOP. This research is one of the scarce studies that follow a holistic approach to understand competitiveness by examining each attribute's company-based and competitor-comparative performance.
•Big data analytics with Importance Performance Competitor Analysis and Asymmetric Impact Competitor Analysis.•Consider symmetric and asymmetric relationships between attributes and satisfaction.•One of the first attempts to examine business-to-business competitiveness in theme park industry.•Ocean Park underperforms Disneyland across attributes.
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