Summary
While therapies targeting the co‐inhibitory or immune checkpoint receptors PD‐1 and CTLA‐4 have shown remarkable success in many cancers, not all patients benefit from these therapies. This ...has catalyzed enormous interest in the targeting of other immune checkpoint receptors. In this regard, TIGIT and CD96 have recently entered the limelight as novel immune checkpoint receptor targets. TIGIT and CD96 together with the co‐stimulatory receptor CD226 form a pathway that is analogous to the CD28/CTLA‐4 pathway, in which shared ligands and differential receptor:ligand affinities fine‐tune the immune response. Although the roles of TIGIT and CD96 as immune checkpoint receptors in T cell and natural killer cell biology are just beginning to be uncovered, accumulating data support the targeting of these receptors for improving anti‐tumor immune responses. A clear understanding of the immune cell populations regulated by TIGIT and CD96 is key to the design of immunotherapies that target these receptors in combination with other existing immune checkpoint blockade therapies.
Coinhibitory receptors, such as CTLA-4 and PD-1, play a critical role in maintaining immune homeostasis by dampening T cell responses. Recently, they have gained attention as therapeutic targets in ...chronic disease settings where their dysregulated expression contributes to suppressed immune responses. The novel coinhibitory receptor TIGIT (T cell Ig and ITIM domain) has been shown to play an important role in modulating immune responses in the context of autoimmunity and cancer. However, the molecular mechanisms by which TIGIT modulates immune responses are still insufficiently understood. We have generated a panel of monoclonal anti-mouse TIGIT Abs that show functional properties in mice in vivo and can serve as important tools to study the underlying mechanisms of TIGIT function. We have identified agonistic as well as blocking anti-TIGIT Ab clones that are capable of modulating T cell responses in vivo. Administration of either agonist or blocking anti-TIGIT Abs modulated autoimmune disease severity whereas administration of blocking anti-TIGIT Abs synergized with anti-PD-1 Abs to affect partial or even complete tumor regression. The Abs presented in this study can thus serve as important tools for detailed analysis of TIGIT function in different disease settings and the knowledge gained will provide valuable insight for the development of novel therapeutic approaches targeting TIGIT.
This study extends the previous brand image measurement processes by using a mixed (qualitative and quantitative) methodology, drawing upon a cognitive approach to represent consumers' minds as a ...network. Therefore, three consecutive studies have been designed from a sample of 1000 passengers to construct four distinct concept maps and a common one pertaining to four Turkish airline companies. The results show the importance of increasing flight comfort, training cabin crew, providing free appetizers, improving service quality, and ensuring timely departures in creating and sustaining a positive brand image. Academicians could use this methodology as an alternative technique to the traditional ones and practitioners could use it to evaluate brands' competitive advantages to create powerful brand images in consumers’ minds.
•A cognitive approach is used to quantify brand image through brand concept maps.•Brand concept maps are created using data from 1000 passengers in Turkey.•Four airline companies' competitive advantages are visualized.•Creating and sustaining brand image requires attention to multiple factors.•Consumers think trustworthiness and good service quality are essential for airlines.
Most effector CD8
T cells die, while some persist and become either "effector" (T
) or "central" (T
) memory T cells. Paradoxically, effector CD8
T cells with greater memory potential have higher ...levels of the pro-apoptotic molecule Bim. Here, we report, using a novel Bim-mCherry knock-in mouse, that cells with high levels of Bim preferentially develop into T
cells. Bim levels remained stable and were regulated by DNA methylation at the Bim promoter. Notably, high levels of Bcl-2 were required for Bim
cells to survive. Using Nur77-GFP mice as an indicator of TCR signal strength, Nur77 levels correlated with Bim expression and Nur77
cells also selectively developed into T
cells. Altogether, these data show that Bim levels and TCR signal strength are predictive of T
- vs. T
-cell fate. Further, given the many other biologic functions of Bim, these mice will have broad utility beyond CD8
T-cell fate.
CD3-engaging bispecific antibodies (BsAbs) enable the formation of an immune synapse between T cells and tumor cells, resulting in robust target cell killing not dependent on a preexisting tumor ...specific T cell receptor. While recent studies have shed light on tumor cell-specific factors that modulate BsAb sensitivity, the T cell-intrinsic determinants of BsAb efficacy and response durability are poorly understood. To better clarify the genes that shape BsAb-induced T cell responses, we conducted targeted analyses and a large-scale unbiased
in vitro
CRISPR/Cas9-based screen to identify negative regulators of BsAb-induced T cell proliferation. These analyses revealed that CD8+ T cells are dependent on CD4+ T cell-derived signaling factors in order to achieve sustained killing
in vitro
. Moreover, the mammalian target of rapamycin (mTOR) pathway and several other candidate genes were identified as intrinsic regulators of BsAb-induced T cell proliferation and/or activation, highlighting promising approaches to enhancing the utility of these potent therapeutics.
BackgroundNIZ985 is a recombinant heterodimer of physiologically active interleukin (IL-)15 and IL-15 receptor alpha. In preclinical models, NIZ985 promotes cytotoxic lymphocyte proliferation, ...killing function, and organ/tumor infiltration, with resultant anticancer effects. In this first-in-human study, we assessed the safety, pharmacokinetics, and immune effects of NIZ985 in patients with metastatic or unresectable solid tumors.MethodsSingle agent NIZ985 dose escalation data are reported from a phase I dose escalation/expansion study of NIZ985 as monotherapy. Adult patients (N=14) received 0.25, 0.5, 1, 2 or 4 µg/kg subcutaneous NIZ985 three times weekly (TIW) for the first 2 weeks of each 28-day cycle, in an accelerated 3+3 dose escalation trial design. IL-15 and endogenous cytokines were monitored by ELISA and multiplexed electrochemiluminescent assays. Multiparameter flow cytometry assessed the frequency, phenotype and proliferation of peripheral blood mononuclear cells. Preliminary antitumor activity was assessed by overall response rate (Response Evaluation Criteria in Solid Tumors V.1.1).ResultsAs of March 2, 2020, median treatment duration was 7.5 weeks (range 1.1–77.1). Thirteen patients had discontinued and one (uveal melanoma) remains on treatment with stable disease. Best clinical response was stable disease (3 of 14 patients; 21%). The most frequent adverse events (AEs) were circular erythematous injection site reactions (100%), chills (71%), fatigue (57%), and fever (50%). Treatment-related grade 3/4 AEs occurred in six participants (43%); treatment-related serious AEs (SAEs) in three (21%). The per-protocol maximum tolerated dose was not reached. Pharmacokinetic accumulation of serum IL-15 in the first week was followed by significantly lower levels in week 2, likely due to more rapid cytokine consumption by an expanding lymphocyte pool. NIZ985 treatment was associated with increases in several cytokines, including interferon (IFN)-γ, IL-18, C-X-C motif chemokine ligand 10, and tumor necrosis factor-β, plus significant induction of cytotoxic lymphocyte proliferation (including natural killer and CD8+ T cells), increased CD16+ monocytes, and increased CD163+ macrophages at injection sites.ConclusionsSubcutaneous NIZ985 TIW was generally well tolerated in patients with advanced cancer and produced immune activation paralleling preclinical observations, with induction of IFN-γ and proliferation of cytotoxic lymphocytes. Due to delayed SAEs at the two highest dose levels, administration is being changed to once-weekly in a revised protocol, as monotherapy and combined with checkpoint inhibitor spartalizumab. These alterations are expected to maximize the potential of NIZ985 as a novel immunotherapy.Trial registration numberNCT02452268.
BackgroundNatural Killer (NK) cells have garnered increasing interest as potential cellular therapies or as targets of biotherapeutic agents due to their ability to kill tumor cells in a non-antigen ...dependent manner. Hence, measurement of NK cell proliferation and/or activation following treatment can serve as a useful biomarker for assessing the efficacy of immunomodulatory therapies.MethodsWe developed a novel 13-parameter flow cytometry panel incorporating cell differentiation (CD) markers important for identification of NK cell subsets (CD56, CD16), their proliferation (Ki-67), activation (CD25, CD335, NKG2D) and inhibition (CD159a) status. Additionally, CD markers that identify other cellular subsets known to be amenable to cytokine modulation (e.g., CD3 and CD14) were included for concurrent monitoring of T cell proliferation and monocyte activation. Method validation focused on analytical sensitivity, specificity and precision as key criteria of assay performance using peripheral blood mononuclear cells (PBMCs) stimulated with NK cell-activating cytokines and resting PBMCs from healthy donors.ResultsThe assay design allowed for robust quantitation of NK cell, T cell and monocyte functionalities. Lower limit of quantification (LLOQ) of target biomarker population was determined to be 1.0% of the parent population, based upon an analysis of 110 key target populations that displayed a co-efficient of variation (CV) of ≤25% and their frequencies ranged from 0.1% to 97.8% of the parent population. Additionally, ≤25% CV was observed in precision assessments, confirming the repeatability and reproducibility of the assay. Clinical trial utility of the assay was verified on cryopreserved PBMCs from patients with a variety of solid tumor malignancies. In these patients, the assay could clearly identify proliferating and activated NK cells, as well as proliferating T cells and activated monocytes, thus demonstrating its suitability for clinical trial applications.ConclusionsWe developed and validated a novel multiparameter flow cytometry assay that allows for simultaneous measurement of proliferation, activation and inhibitory status of key immune cell subsets. Thus, this assay can help shed light on the mode of efficacy of novel therapeutic agents that modulate the immune system, aimed at treatment of cancer and autoimmune diseases.
Purpose This study aims to identify the role of consumer characteristics in cultural consumption tendencies. Additionally, the study examines whether country differences and prior experience in the ...country affect consumers' cultural consumption tendencies. Design/methodology/approach The effects of cosmopolitanism, consumer ethnocentrism, individual innovativeness, and lifestyle on cultural consumption tendencies were tested. Moreover, we assess whether country type and prior experience are differentiating factors for cultural consumption tendencies. To this end, two countries – the USA and South Korea, representing Western and Eastern cultures, respectively – were selected to achieve comparable results in two different cultures. The research data were collected from 775 people using an online survey method and analyzed using path analysis and an independent samples t -test. Findings Consumer characteristics affect cultural consumption tendencies. These effects are culture-specific and cultural product-specific. Cosmopolitanism has a positive impact on cultural consumption tendencies, while consumer ethnocentrism has a negative impact. Individual innovativeness and lifestyle partially affected cultural consumption tendencies. Notably, these effects differ by country type. However, cultural consumption tendencies do not differ according to consumers' prior experience. Practical implications This study provides insightful information for e-retailers to be mindful of global consumer characteristics. Accordingly, cultural consumption patterns can be used as the basis for market segmentation. In addition, understanding global consumer characteristics and their cultural product- and culture-specific effects on consumption will help cultural industry players in their segmentation and targeting decisions. Originality/value Notwithstanding the rich body of literature on cultural consumption, this study provides consumer-level comparative empirical research from a marketing perspective. Essentially, the study is novel as it reveals the consumer characteristics that affect cultural consumption tendencies.
An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the ...effector response of CD8+ tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1− TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7/Tcf1 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8+ T cell responses upon immunotherapy.
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•Checkpoint blockade induces transcriptional changes in PD-1−CD8+ and PD-1+CD8+ TILs•PD-1−CD8+ TILs contain naive-, memory-precursor-, and effector-like subsets•Memory-precursor- and effector-like PD-1−CD8+ TILs expand upon checkpoint blockade•Tcf7 is required for memory-precursor-like cells and efficacy of immunotherapies
Kurtulus et al. examine the dynamics of the effector CD8+ T cell response in the tumor microenvironment in response to checkpoint blockade immunotherapy. Checkpoint blockade induced a shift from naive-like to memory-precursor- and effector-like subsets within PD-1−CD8+ T cells in tumors. The memory-precursor-like subset is maintained by the transcriptional regulator Tcf7/Tcf1, which is required for efficacy of checkpoint blockade and other immunotherapies.
The main aim of this study is to determine the roles of environmental consciousness, lifestyle and involvement factors on purchasing behavior. Factors affecting environmentally friendly behaviors ...were explained within the context of attitude, intention and behavior with a holistic approach. TRA Model (Theory of Reasoned Action) was expanded by adding variables that express individual consumer characteristics.
Data were gathered via face to face survey from 900 participants who live in Istanbul where people from different socio-economic backgrounds are thought to be located. The proposed model was analyzed by means of Structural Equation Modelling.
According to results, environmental consciousness, lifestyle and involvement factors have significant impacts upon attitude and intention towards buying. Also, behavioral dimension of environmental consciousness (such as recycling) and purchasing intention have the greatest impact upon buying behavior.
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