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This paper illustrates that immunosurveillance and immunoediting can occur in an oncogene-driven endogenous tumour model provided that the tumours carry strong neoantigens not present in the host. The anticancer potential of immunoediting Two groups reporting in this issue of Nature use contrasting approaches to come to many of the same conclusions about the process of cancer immunoediting, in which an individual is protected from cancer though the elimination and immunogenic modification of cancerous cells. Matsushita et al . use whole-exon sequencing of mouse sarcomas induced by chemical carcinogens to obtain evidence for T-cell-mediated immuno-selection as a mechanism of immune editing. DuPage et al . demonstrate that immunosurveillance and immunoediting can occur in an oncogene-driven endogenous tumour model provided that the tumours carry strong neoantigens that are not present in the host. Cancer immunoediting is a process by which immune cells, particularly lymphocytes of the adaptive immune system, protect the host from the development of cancer and alter tumour progression by driving the outgrowth of tumour cells with decreased sensitivity to immune attack 1 , 2 . Carcinogen-induced mouse models of cancer have shown that primary tumour susceptibility is thereby enhanced in immune-compromised mice, whereas the capacity for such tumours to grow after transplantation into wild-type mice is reduced 2 , 3 . However, many questions about the process of cancer immunoediting remain unanswered, in part because of the known antigenic complexity and heterogeneity of carcinogen-induced tumours 4 . Here we adapted a genetically engineered, autochthonous mouse model of sarcomagenesis to investigate the process of cancer immunoediting. This system allows us to monitor the onset and growth of immunogenic and non-immunogenic tumours induced in situ that harbour identical genetic and histopathological characteristics. By comparing the development of such tumours in immune-competent mice with their development in mice with broad immunodeficiency or specific antigenic tolerance, we show that recognition of tumour-specific antigens by lymphocytes is critical for immunoediting against sarcomas. Furthermore, primary sarcomas were edited to become less immunogenic through the selective outgrowth of cells that were able to escape T lymphocyte attack. Loss of tumour antigen expression or presentation on major histocompatibility complex I was necessary and sufficient for this immunoediting process to occur. These results highlight the importance of tumour-specific-antigen expression in immune surveillance, and potentially, immunotherapy.

A subset of Kras and p53 mutant cancer cells acts as a Wnt-producing niche for another cancer cell subset, and porcupine inhibition disrupts Wnt secretion in this niche, thereby suppressing proliferative potential and leading to therapeutic benefit. Lung cancer niche drives tumour growth Lung adenocarcinomas are aggressive tumours which are associated with poor treatment outcome. Tyler Jacks and colleagues now show that lung adenocarcinomas display two distinct subpopulations of tumour cells. One of these shows high levels of Wnt signalling and gives rise to the second one that produces Wnt ligands. The latter population fuels tumour growth of the former, showing that lung cancer cells can produce their own niche. These findings shed new light on the mechanisms underlying intratumoural heterogeneity which may have therapeutic implications. The heterogeneity of cellular states in cancer has been linked to drug resistance, cancer progression and the presence of cancer cells with properties of normal tissue stem cells 1 , 2 . Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration 3 , 4 , 5 . Here we show that mouse and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signalling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that these cells have features of normal tissue stem cells. Genetic perturbation of Wnt production or signalling suppressed tumour progression. Small-molecule inhibitors targeting essential posttranslational modification of Wnt reduced tumour growth and markedly decreased the proliferative potential of lung cancer cells, leading to improved survival of tumour-bearing mice. These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies.

Natural killer (NK) cells inhibit tumor development in mouse models and their presence in tumors correlates with patient survival. However, tumor-associated NK cells become dysfunctional; thus, stimulation of NK cells in cancer is emerging as an attractive immunotherapeutic strategy. In a mouse model of lung adenocarcinoma, NK cells localized to tumor stroma with immature phenotypes and low functional capacity. To test their responsiveness within established disease,we engineered a system for inducible expression of activating ligands in tumors. After stimulation, NK cells localized inside tumors, with increased cytokine production capacity. Strikingly, T cells were also recruited to tumors in an NK cell-dependent manner, and exhibited higher functionality. In neoantigen-expressing tumors, NK cell stimulation enhanced the number and function of tumor-specific T cells and, in long-term settings, reduced tumor growth. Thus, even in established disease NK cells can be activated to contribute to antitumor immunity, supporting their potential as an important target in cancer immunotherapy.

Inducible expression of neoantigens in mice would enable the study of endogenous antigen-specific naïve T cell responses in disease and infection, but has been difficult to generate because leaky antigen expression in the thymus results in central T cell tolerance. Here we develop inversion-induced joined neoantigen (NINJA), using RNA splicing, DNA recombination and three levels of regulation to prevent leakiness and allow tight control over neoantigen expression. We apply NINJA to create tumor cell lines with inducible neoantigen expression, which could be used to study antitumor immunity. We also show that the genetic regulation in NINJA mice bypasses central and peripheral tolerance mechanisms and allows for robust endogenous CD8 and CD4 T cell responses on neoantigen induction in peripheral tissues. NINJA will enable studies of how T cells respond to defined neoantigens in the context of peripheral tolerance, transplantation, autoimmune diseases and cancer. A system to express neoantigens in tumor cells and mice circumvents central T cell tolerance.

Cancer immunoediting is a process by which immune cells, particularly lymphocytes of the adaptive immune system, protect the host from the development of cancer and alter tumour progression by driving the outgrowth of tumour cells with decreased sensitivity to immune attack (1,2). Carcinogen-induced mouse models of cancer have shown that primary tumour susceptibility is thereby enhanced in immune-compromised mice, whereas the capacity for such tumours to grow after transplantation into wild-type mice is reduced (2,3). However, many questions about the process of cancer immunoediting remain unanswered, in part because of the known antigenic complexity and heterogeneity of carcinogen-induced tumours (4). Here we adapted agenetically engineered, autochthonous mouse model of sarcomagenesis to investigate the process of cancer immunoediting. This system allows us to monitor the onset and growth of immunogenic and non-immunogenic tumours induced in situ that harbour identical genetic and histopathological characteristics. By comparing the development of such tumours in immune-competent mice with their development in mice with broad immunodeficiency or specific antigenic tolerance, we show that recognition of tumour-specific antigens by lymphocytes is critical for immunoediting against sarcomas. Furthermore, primary sarcomas were edited to become less immunogenic through the selective outgrowth of cells that were able to escape T lymphocyte attack. Loss of tumour antigen expression or presentation on major histocompatibility complex I was necessary and sufficient for this immunoediting process to occur. These results highlight the importance of tumour-specific-antigen expression in immune surveillance, and potentially, immunotherapy.

Over the past five decades, US policymakers have rationalized school consolidation as a vehicle of educational equity. Nevertheless, educators, parents, and community leaders remain divided regarding its impact on low-income, minority student populations; and critics have observed that school consolidation based on the premise of educational equity has often resulted in upheaval for minority and economically disadvantaged children, their families, and their communities. Daugherty Schmidt describes consolidation efforts that were implemented in the public schools of Warren, Ohio, between 1978 and 2011. While school consolidation in the Warren City Schools was rationalized as an attempt to eliminate de facto desegregation and promote educational equity, the initial consolidation plans were reactions to dwindling enrollments and budgetary shortfalls following widespread deindustrialization.

Inducible expression of neoantigens in mice would enable the study of endogenous antigen-specific naïve T cell responses in disease and infection, but has been difficult to generate because leaky antigen expression in the thymus results in central T cell tolerance. Here, we developed iNversion INduced Joined neoAntigen (NINJA), using RNA splicing, DNA recombination, and three levels of regulation to prevent leakiness and allow tight control over neoantigen expression. We apply NINJA to create tumor cell lines with inducible neoantigen expression, which could be used to study anti-tumor immunity. We also show that the genetic regulation in NINJA mice bypasses central and peripheral tolerance mechanisms and allows for robust endogenous CD8 and CD4 T cells responses upon neoantigen induction in peripheral tissues. NINJA will enable studies of how T cells respond to defined neoantigens in the context of peripheral tolerance, transplantation, autoimmune diseases, and cancer.

Mouse models with inducible neoantigens have been historically difficult to generate because of leaky expression of antigens in the thymus, which causes central tolerance in developing CD8 and CD4 T cells. Attempts to resolve this problem using existing genetic tools have been unsuccessful. We developed the iNversion INducible Joined neoAntigen (NINJA) mouse model that uses RNA splicing, DNA recombination, and three levels of regulation to prevent neoantigen leakiness and allow tight control over the induction of neoantigen expression. We describe the development of these genetic tools and their use for obtaining tumor cell lines with inducible neoantigen expression. Moreover, we show that the genetic regulation in NINJA mice bypasses central and peripheral tolerance mechanisms and allows for robust endogenous CD8 and CD4 T cells responses upon neoantigen induction in peripheral tissues. Thus, NINJA fills a long-standing gap in the field and will enable studies of how T cells respond to defined neoantigens in the context of peripheral tolerance, autoimmune diseases, and developing tumors.

This study is an inquiry into the possibilities and limitations of school consolidations. The study begins by exploring the history of school reorganization from the common school movement to the present. From this history we learn that unchallenged assumptions regarding school consolidations and efficiency and effectiveness gains have thrived. My research draws attention to the scarcity of post-consolidation studies that provide discernable evidence that either school or district consolidations have resulted in enhanced efficiencies or effectiveness. Difference-in-Difference (DiD) Estimation calculations were performed on national and state data looking for evidence that consolidations improved efficiencies or effectiveness. The results are inconclusive. Thrown into the mix of efficiency and effectiveness goals was consolidation for equity, which came into play in the 1960s. The study of consolidation through the lens of equity shows that desegregation and fiscal considerations have remained the foci of the pursuit of equal educational opportunity, for about fifty years. Looking at the Warren City School District’s consolidation experience over the past three decades, we see that consolidation based on the premise of educational equity has often resulted in upheaval for minority and economically disadvantaged children, their families, and their communities. The elusive concept of local control of schooling is examined to ascertain whether local control can act as a bulwark against consolidation efforts. We learn that there is no consensus concerning what local control means, at what level it exists, and who actually does the local controlling. Furthermore, we see that the state has extraordinary powers to wrest any local control that a community may enjoy. The study concludes with an exploration of the significance of neighborhood and local schools in struggling communities. Consolidation too often removes schools from the most fragile of communities, resulting in further degradation of poor and minority neighborhoods. The experience of the extinct Farmington School District and the boarded up West Farmington Elementary School provide insight into what happens to a community without a school.

The ability to control one’s own emotions, thoughts, and behaviors in early life predicts a range of positive outcomes in later life, including longevity. Does it also predict how well people age? We studied the association between self-control and midlife aging in a population-representative cohort of children followed from birth to age 45 y, the Dunedin Study. We measured children’s self-control across their first decade of life using a multi-occasion/multiinformant strategy. We measured their pace of aging and aging preparedness in midlife using measures derived from biological and physiological assessments, structural brain-imaging scans, observer ratings, self-reports, informant reports, and administrative records. As adults, children with better self-control aged more slowly in their bodies and showed fewer signs of aging in their brains. By midlife, these children were also better equipped to manage a range of later-life health, financial, and social demands. Associations with children’s self-control could be separated from their social class origins and intelligence, indicating that self-control might be an active ingredient in healthy aging. Children also shifted naturally in their level of self-control across adult life, suggesting the possibility that self-control may be a malleable target for intervention. Furthermore, individuals’ self-control in adulthood was associated with their aging outcomes after accounting for their self-control in childhood, indicating that midlife might offer another window of opportunity to promote healthy aging.