The two-player Iterated Prisoner’s Dilemma game is a model for both sentient and evolutionary behaviors, especially including the emergence of cooperation. It is generally assumed that there exists ...no simple ultimatum strategy whereby one player can enforce a unilateral claim to an unfair share of rewards. Here, we show that such strategies unexpectedly do exist. In particular, a player X who is witting of these strategies can (i) deterministically set her opponent Y’s score, independently of his strategy or response, or (ii) enforce an extortionate linear relation between her and his scores. Against such a player, an evolutionary player’s best response is to accede to the extortion. Only a player with a theory of mind about his opponent can do better, in which case Iterated Prisoner’s Dilemma is an Ultimatum Game.
Targeting immune checkpoints such as programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has achieved noteworthy benefit in ...multiple cancers by blocking immunoinhibitory signals and enabling patients to produce an effective antitumour response. Inhibitors of CTLA4, PD1 or PDL1 administered as single agents have resulted in durable tumour regression in some patients, and combinations of PD1 and CTLA4 inhibitors may enhance antitumour benefit. Numerous additional immunomodulatory pathways as well as inhibitory factors expressed or secreted by myeloid and stromal cells in the tumour microenvironment are potential targets for synergizing with immune checkpoint blockade. Given the breadth of potential targets in the immune system, critical questions to address include which combinations should move forward in development and which patients will benefit from these treatments. This Review discusses the leading drug targets that are expressed on tumour cells and in the tumour microenvironment that allow enhancement of the antitumour immune response.
The microsatellite instable (MSI) subset of colorectal cancer exhibits an active Th1/CTL immune microenvironment, probably due to recognition of a high number of tumor neoantigens. However, the high ...expression of checkpoint molecules PD-1, PD-L1, CTLA-4, LAG-3, and IDO in MSI colorectal cancer distinguishes MSI from microsatellite stable colorectal cancer and creates an immunosuppressive microenvironment that may help MSI tumors evade immune destruction by the infiltrating immune cells. Though colorectal cancer does not have a good response rate to PD-1 pathway immunotherapy, these results suggest that the MSI subset of colorectal cancer is a particularly good candidate for checkpoint immunotherapy.
Allergic asthma is caused by Th2-cell-type cytokines in response to allergen exposure. Type 2 innate lymphoid cells (ILC2s) are a newly identified subset of immune cells that, along with Th2 cells, ...contribute to the pathogenesis of asthma by producing copious amounts of IL-5 and IL-13, which cause eosinophilia and airway hyperreactivity (AHR), a cardinal feature of asthma. ILC2s express ICOS, a T cell costimulatory molecule with a currently unknown function. Here we showed that a lack of ICOS on murine ILC2s and blocking the ICOS:ICOS-ligand interaction in human ILC2s reduced AHR and lung inflammation. ILC2s expressed both ICOS and ICOS-ligand, and the ICOS:ICOS-ligand interaction promoted cytokine production and survival in ILC2s through STAT5 signaling. Thus, ICOS:ICOS-ligand signaling pathway is critically involved in ILC2 function and homeostasis.
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•Human and murine ILC2s express both ICOS and ICOS-ligand•The ICOS:ICOS-ligand interaction is required for survival and efficient function of ILC2s•STAT5 signaling is impaired in the absence of ICOS
Akbari and colleagues show the requirement of Inducible T cell Costimulator (ICOS) for the survival and efficient cytokine production of type 2 innate lymphoid cells (ILC2s), which are key players in the pathogenesis of allergic asthma.
Immune responses need to be controlled for optimal protective immunity and tolerance. Coinhibitory pathways in the B7-CD28 family provide critical inhibitory signals that regulate immune homeostasis ...and defense and protect tissue integrity. These coinhibitory signals limit the strength and duration of immune responses, thereby curbing immune-mediated tissue damage, regulating resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors and microbes that cause chronic infections can exploit these coinhibitory pathways to establish an immunosuppressive microenvironment, hindering their eradication. Advances in understanding T cell coinhibitory pathways have stimulated a new era of immunotherapy with effective drugs to treat cancer, autoimmune and infectious diseases, and transplant rejection. In this review we discuss the current knowledge of the mechanisms underlying the coinhibitory functions of pathways in the B7-CD28 family, the diverse functional consequences of these inhibitory signals on immune responses, and the overlapping and unique functions of these key immunoregulatory pathways.
Coinhibitory pathways in the B7-CD28 family provide critical inhibitory signals that regulate immune homeostasis and defense. Sharpe and colleagues discuss the current understanding of mechanisms underlying the coinhibitory functions of pathways in the B7-CD28 family, their functional consequences, and their overlapping and unique functions.
In the wake of the success of modern immunotherapy, oncolytic viruses (OVs) are currently seen as a potential therapeutic option for patients with cancer who do not respond or fail to achieve durable ...responses following treatment with immune checkpoint inhibitors. OVs offer a multifaceted therapeutic platform because they preferentially replicate in tumour cells, can be engineered to express transgenes that augment their cytotoxic and immunostimulatory activities, and modulate the tumour microenvironment to optimize immune-mediated tumour eradication, both at locoregional and systemic sites of disease. Lysis of tumour cells releases tumour-specific antigens that trigger both the innate and adaptive immune systems. OVs also represent attractive combination partners with other systemically delivered agents by virtue of their highly favourable safety profiles. Rational combinations of OVs with different immune modifiers and/or antitumour agents, based on mechanisms of tumour resistance to immune-mediated attack, may benefit the large, currently underserved, population of patients who respond poorly to immune checkpoint inhibition.
Spin-orbit coupling can induce spin polarization in nonmagnetic 3D crystals when the inversion symmetry is broken, as manifested by the bulk Rashba and Dresselhaus effects. We establish that these ...spin-polarization effects originate fundamentally from specific atomic site asymmetries, rather than, as generally accepted, from the asymmetry of the crystal space group. This understanding leads to the recognition that a previously overlooked hidden form of spin polarization should exist in centrosymmetric crystals. Although all energy bands must be doubly degenerate in centrosymmetric materials, we find that the two components of such doubly degenerate bands could have opposite polarizations, each spatially localized on one of the two separate sectors forming the inversion partners. We demonstrate such hidden spin polarizations in particular centrosymmetric crystals by first-principles calculations. This new understanding could considerably broaden the range of currently useful spintronic materials and enable the control of spin polarization by means of operations on the atomic scale.
Misinformation about COVID-19 is a major threat to public health. Using five national samples from the UK (
1050 and
1150), Ireland (
= 700), the USA (
= 700), Spain (
700) and Mexico (
700), we ...examine predictors of belief in the most common statements about the virus that contain misinformation. We also investigate the prevalence of belief in COVID-19 misinformation across different countries and the role of belief in such misinformation in predicting relevant health behaviours. We find that while public belief in misinformation about COVID-19 is not particularly common, a substantial proportion views this type of misinformation as highly reliable in each country surveyed. In addition, a small group of participants find common factual information about the virus highly unreliable. We also find that increased susceptibility to misinformation negatively affects people's self-reported compliance with public health guidance about COVID-19, as well as people's willingness to get vaccinated against the virus and to recommend the vaccine to vulnerable friends and family. Across all countries surveyed, we find that higher trust in scientists and having higher numeracy skills were associated with lower susceptibility to coronavirus-related misinformation. Taken together, these results demonstrate a clear link between susceptibility to misinformation and both vaccine hesitancy and a reduced likelihood to comply with health guidance measures, and suggest that interventions which aim to improve critical thinking and trust in science may be a promising avenue for future research.
As part of the Systematizing Confidence in Open Research and Evidence (SCORE) program, the present study consisted of a two-stage replication test of a central finding by Pennycook et al. (2020), ...namely that asking people to think about the accuracy of a single headline improves “truth discernment” of intentions to share news headlines about COVID-19. The first stage of the replication test (n = 701) was unsuccessful (p = .67). After collecting a second round of data (additional n = 882, pooled N = 1,583), we found a small but significant interaction between treatment condition and truth discernment (uncorrected p = .017; treatment: d = 0.14, control: d = 0.10). As in the target study, perceived headline accuracy correlated with treatment impact, so that treatment-group participants were less willing to share headlines that were perceived as less accurate. We discuss potential explanations for these findings and an unreported change in the hypothesis (but not the analysis plan) from the preregistration in the original study.
The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. ...Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer.
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