Consumers seek naturalness across many domains, including physical appearance. It seems that the desire for natural beauty would discourage artificial appearance-enhancement consumption, such as ...cosmetic use. However, across an analysis of the “no-makeup movement” on Twitter and Nielsen cosmetic sales (Study 1a), an image analysis of #nomakeup selfies using machine learning approaches (Study 1b), and three experiments (Studies 2–4), we find that calls to look natural can be associated with increased artificial beauty practices. Drawing from attribution theory, we theorize that calls to look natural maintain the value of attractiveness while adding the consumer concern that others will discount their attractiveness if overt effort is present. Thus, rather than investing less effort, consumers may engage in a self-presentational strategy wherein they
construct
an appearance of naturalness to signal low effort to others, thereby augmenting their attractiveness. This work contributes to attribution and self-presentation theory and offers practical implications for naturalness consumption.
Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX2/PGE
/EP2-4 pathway with widely ...used nonsteroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to distinguish responders from nonresponders shortly after treatment and identified acute IFNγ-driven transcriptional remodeling in responder mice, which was also associated with patient benefit to ICB. Monotherapy with COX2 inhibitors or EP2-4 PGE
receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of effector T cells. Treatment of patient-derived tumor fragments from multiple cancer types revealed a similar shift in the tumor inflammatory environment to favor T-cell activation. Our findings establish the COX2/PGE
/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to rapidly switch the tumor inflammatory profile from cold to hot. SIGNIFICANCE: Through performing in-depth profiling of mice and human tumors, this study identifies mechanisms by which anti-inflammatory drugs rapidly alter the tumor immune landscape to enhance tumor immunogenicity and responses to immune checkpoint inhibitors.
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A number of immunotherapies, in particular immune checkpoint targeting antibodies and adoptive T-cell therapies, are starting to transform the treatment of advanced cancers. The likelihood to respond ...to these immunotherapies differs strongly across tumor types, with response rates for checkpoint targeting being the highest in advanced melanoma, renal cell cancer and non-small cell lung cancer. However, also non-responsiveness is observed, indicating the presence of intrinsic resistance or naturally acquired resistance. In addition, a subgroup of patients that do initially respond to immunotherapy will later recur, thereby also pointing towards a role of therapy-induced acquired resistance.
Here, we review our current understanding of both intrinsic and acquired resistance mechanisms in cancer immunotherapy, and discuss potential strategies to overcome them.
•Intrinsic and acquired immune resistance determine the efficiency of cancer immunotherapy.•An effective immune response requires T-cell activation, homing and effector function.•The development of immune resistance can be evaluated on the basis on these three requirements.•A personalized approach to assess immune resistance is likely to increase the efficacy of immunotherapy.
The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high ...proportion of patients in two small independent early-phase trials, and no patients with a pathological response have relapsed after a median follow up of 32 months. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo trial was to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective.
OpACIN-neo is a multicentre, open-label, phase 2, randomised, controlled trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0–1, had resectable stage III melanoma involving lymph nodes only, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients were enrolled from three medical centres in Australia, Sweden, and the Netherlands, and were randomly assigned (1:1:1), stratified by site, to one of three neoadjuvant dosing schedules: group A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks intravenously; group B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously; or group C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3 mg/kg once every 2 weeks intravenously. The investigators, site staff, and patients were aware of the treatment assignment during the study participation. Pathologists were masked to treatment allocation and all other data. The primary endpoints were the proportion of patients with grade 3–4 immune-related toxicity within the first 12 weeks and the proportion of patients achieving a radiological objective response and pathological response at 6 weeks. Analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02977052, and is ongoing with an additional extension cohort and to complete survival analysis.
Between Nov 24, 2016 and June 28, 2018, 105 patients were screened for eligibility, of whom 89 (85%) eligible patients were enrolled and randomly assigned to one of the three groups. Three patients were excluded after randomisation because they were found to be ineligible, and 86 received at least one dose of study drug; 30 patients in group A, 30 in group B, and 26 in group C (accrual to this group was closed early upon advice of the Data Safety Monitoring Board on June 4, 2018 because of severe adverse events). Within the first 12 weeks, grade 3–4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. The difference in grade 3–4 toxicity between group B and A was −20% (95% CI −46 to 6; p=0·158) and between group C and group A was 10% (−20 to 40; p=0·591). The most common grade 3–4 adverse events were elevated liver enzymes in group A (six 20%)) and colitis in group C (five 19%); in group B, none of the grade 3–4 adverse events were seen in more than one patient. One patient (in group A) died 9·5 months after the start of treatment due to the consequences of late-onset immune-related encephalitis, which was possibly treatment-related. 19 (63% 95% CI 44–80) of 30 patients in group A, 17 (57% 37–75) of 30 in group B, and nine (35% 17–56) of 26 in group C achieved a radiological objective response, while pathological responses occurred in 24 (80% 61–92) patients in group A, 23 (77% 58–90) in group B, and 17 (65% 44–83) in group C.
OpACIN-neo identified a tolerable neoadjuvant dosing schedule (group B: two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg) that induces a pathological response in a high proportion of patients and might be suitable for broader clinical use. When more mature data confirm these early observations, this schedule should be tested in randomised phase 3 studies versus adjuvant therapies, which are the current standard-of-care systemic therapy for patients with stage III melanoma.
Bristol-Myers Squibb.
The magnitude of antigen-specific CD8⁺ T cell responses is not fixed but correlates with the severity of infection. Although by definition T cell response size is the product of both the capacity to ...recruit naïve T cells (clonal selection) and their subsequent proliferation (clonal expansion), it remains undefined how these two factors regulate antigen-specific T cell responses. We determined the relative contribution of recruitment and expansion by labeling naïve T cells with unique genetic tags and transferring them into mice. Under disparate infection conditions with different pathogens and doses, recruitment of antigen-specific T cells was near constant and close to complete. Thus, naïve T cell recruitment is highly efficient, and the magnitude of antigen-specific CD8⁺ T cell responses is primarily controlled by clonal expansion.
Recognition of neoantigens that are formed as a consequence of DNA damage is likely to form a major driving force behind the clinical activity of cancer immunotherapies such as T-cell checkpoint ...blockade and adoptive T-cell therapy. Therefore, strategies to selectively enhance T-cell reactivity against genetically defined neoantigens are currently under development. In mouse models, T-cell pressure can sculpt the antigenicity of tumours, resulting in the emergence of tumours that lack defined mutant antigens. However, whether the T-cell-recognized neoantigen repertoire in human cancers is constant over time is unclear. Here we analyse the stability of neoantigen-specific T-cell responses and the antigens they recognize in two patients with stage IV melanoma treated by adoptive T-cell transfer. The T-cell-recognized neoantigens can be selectively lost from the tumour cell population, either by overall reduced expression of the genes or loss of the mutant alleles. Notably, loss of expression of T-cell-recognized neoantigens was accompanied by development of neoantigen-specific T-cell reactivity in tumour-infiltrating lymphocytes. These data demonstrate the dynamic interactions between cancer cells and T cells, which suggest that T cells mediate neoantigen immunoediting, and indicate that the therapeutic induction of broad neoantigen-specific T-cell responses should be used to avoid tumour resistance.
Formation of Tissue-Resident CD8 + T-Cell Memory Dijkgraaf, Feline E; Kok, Lianne; Schumacher, Ton N M
Cold Spring Harbor perspectives in biology,
08/2021, Volume:
13, Issue:
8
Journal Article
Peer reviewed
Open access
Resident memory CD8
T (Trm) cells permanently reside in nonlymphoid tissues where they act as a first line of defense against recurrent pathogens. How and when antigen-inexperienced CD8
T cells ...differentiate into Trm has been a topic of major interest, as knowledge on how to steer this process may be exploited in the development of vaccines and anticancer therapies. Here, we first review the current understanding of the early signals that CD8
T cells receive before they have entered the tissue and that govern their capacity to develop into tissue-resident memory T cells. Subsequently, we discuss the tissue-derived factors that promote Trm maturation in situ. Combined, these data sketch a model in which a subset of responding T cells develops a heightened capacity to respond to local cues present in the tissue microenvironment, which thereby imprints their ability to contribute to the tissue-resident memory CD8
T-cell pool that provide local control against pathogens.
Major developmental processes such as gastrulation and early embryogenesis rely on a complex network of cell–cell interactions, chromatin remodeling, and transcriptional regulators. This makes it ...challenging to study early development when using bulk populations of cells. Recent advances in single-cell technologies have allowed researchers to better understand the interactions between different molecular modalities and the heterogeneities within classically defined cell types. As new single-cell technologies mature, they have the potential of providing a step-change in our understanding of embryogenesis. In this review, we summarize recent advances in single-cell technologies with particular focus on those that lend insight into early organogenesis. We then discuss current pitfalls and implications for future research.
Among the most prevalent neurodevelopmental disorders, Autism Spectrum Disorder (ASD) is highly diverse showing a broad phenotypic spectrum. ASD also couples with a broad range of mutations, both de ...novo and inherited. In this study, we used a proprietary SNP genotyping chip to analyze the genomic DNA of 250 Vietnamese children diagnosed with ASD. Our Single Nucleotide Polymorphism (SNP) genotyping chip directly targets more than 800 thousand SNPs in the genome. Our primary focus was to identify pathogenic/likely pathogenic mutations that are potentially linked to more severe symptoms of autism. We identified and validated 23 pathogenic/likely pathogenic mutations in this initial study. The data shows that these mutations were detected in several cases spanning multiple biological pathways. Among the confirmed SNPs, mutations were identified in genes previously known to be strongly associated with ASD such as SLCO1B1, ACADSB, TCF4, HCP5, MOCOS, SRD5A2, MCCC2, DCC, and PRKN while several other mutations are known to associate with autistic traits or other neurodevelopmental disorders. Some mutations were found in multiple patients and some patients carried multiple pathogenic/likely pathogenic mutations. These findings contribute to the identification of potential targets for therapeutic solutions in what is considered a genetically heterogeneous neurodevelopmental disorder.
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