The monoclonal antibodies ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have shown remarkable antitumor activity in an increasing number of cancers. When combined, ipilimumab and nivolumab have ...demonstrated superior activity in patients with metastatic melanoma (CHECKMATE-067). Here we describe the preclinical development strategy that predicted these clinical results. Synergistic antitumor activity in mouse MC38 and CT26 colorectal tumor models was observed with concurrent, but not sequential CTLA-4 and PD-1 blockade. Significant antitumor activity was maintained using a fixed dose of anti-CTLA-4 antibody with decreasing doses of anti-PD-1 antibody in the MC38 model. Immunohistochemical and flow cytometric analyses confirmed that CD3+ T cells accumulated at the tumor margin and infiltrated the tumor mass in response to the combination therapy, resulting in favorable effector and regulatory T-cell ratios, increased pro-inflammatory cytokine secretion, and activation of tumor-specific T cells. Similarly, in vitro studies with combined ipilimumab and nivolumab showed enhanced cytokine secretion in superantigen stimulation of human peripheral blood lymphocytes and in mixed lymphocyte response assays. In a cynomolgus macaque toxicology study, dose-dependent immune-related gastrointestinal inflammation was observed with the combination therapy; this response had not been observed in previous single agent cynomolgus studies. Together, these in vitro assays and in vivo models comprise a preclinical strategy for the identification and development of highly effective antitumor combination immunotherapies.
Stochastic mechanisms diversify cell fates during development. How cells randomly choose between two or more fates remains poorly understood. In the Drosophila eye, the random mosaic of two R7 ...photoreceptor subtypes is determined by expression of the transcription factor Spineless (Ss). We investigated how cis-regulatory elements and trans factors regulate nascent transcriptional activity and chromatin compaction at the ss gene locus during R7 development. The ss locus is in a compact state in undifferentiated cells. An early enhancer drives transcription in all R7 precursors, and the locus opens. In differentiating cells, transcription ceases and the ss locus stochastically remains open or compacts. In SsON R7s, ss is open and competent for activation by a late enhancer, whereas in SsOFF R7s, ss is compact, and repression prevents expression. Our results suggest that a temporally dynamic antagonism, in which transcription drives large-scale decompaction and then compaction represses transcription, controls stochastic fate specification.
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•spineless is off, and the locus is in a compact state in undifferentiated cells•The early enhancer drives expression, and the locus opens•Expression ceases, and the locus recompacts or remains open•Repression in a subset of R7s limits expression driven by the late enhancer
Cells sometimes randomly choose between fates during development. In Drosophila, a random mosaic of photoreceptor subtypes is determined by the spineless gene. Voortman et al. find that spineless is regulated by a dynamic interplay between transcription and chromatin compaction during fly eye development.
America has a long tradition of middle-class radicalism, albeit one that intellectual orthodoxy has tended to obscure.The Radical Middle Classseeks to uncover the democratic, populist, and even ...anticapitalist legacy of the middle class. By examining in particular the independent small business sector or petite bourgeoisie, using Progressive Era Portland, Oregon, as a case study, Robert Johnston shows that class still matters in America. But it matters only if the politics and culture of the leading player in affairs of class, the middle class, is dramatically reconceived.
This book is a powerful combination of intellectual, business, labor, medical, and, above all, political history. Its author also humanizes the middle class by describing the lives of four small business owners: Harry Lane, Will Daly, William U'Ren, and Lora Little. Lane was Portland's reform mayor before becoming one of only six senators to vote against U.S. entry into World War I. Daly was Oregon's most prominent labor leader and a onetime Socialist. U'Ren was the national architect of the direct democracy movement. Little was a leading antivaccinationist.
The Radical Middle Classfurther explores the Portland Ku Klux Klan and concludes with a national overview of the American middle class from the Progressive Era to the present. With its engaging narrative, conceptual richness, and daring argumentation, it will be welcomed by all who understand that reexamining the middle class can yield not only better scholarship but firmer grounds for democratic hope.
James Colgrove is one of the nation's most important historians of vaccine politics, and his scholarship always speaks compellingly to issues related to vaccination policy and ethics.1 He and SaraJ. ...Samuel have produced an article that insightfully reveals how and why history truly matters as we seek to explain the wide scope, and the tenacity, of vaccine refusal throughout US history. Indeed, the COVID-19 pandemic arguably makes this history matter more in our current moment than at any other time in the past. Simply put: we cannot explain the current widespread and deadly resistance in the United States to the Pfizer/ BioNTech, Moderna, and Johnson and Johnson vaccines-and the various mandates associated with these vaccines- without understanding the long roots of outright opposition to vaccination mandates (along with vaccination itself) throughout American history. In this issue of AJPH, Colgrove and Samuel rightly point to the centrality of the period from the 1880s to the 1920s, when vaccination dissidence was at its height and when discourses of freedom and rights were central to opposition to modern public health policies.
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Tumors constitute highly suppressive microenvironments in which infiltrating T cells are “exhausted” by inhibitory receptors such as PD-1. Here we identify TIGIT as a coinhibitory receptor that ...critically limits antitumor and other CD8+ T cell-dependent chronic immune responses. TIGIT is highly expressed on human and murine tumor-infiltrating T cells, and, in models of both cancer and chronic viral infection, antibody coblockade of TIGIT and PD-L1 synergistically and specifically enhanced CD8+ T cell effector function, resulting in significant tumor and viral clearance, respectively. This effect was abrogated by blockade of TIGIT’s complementary costimulatory receptor, CD226, whose dimerization is disrupted upon direct interaction with TIGIT in cis. These results define a key role for TIGIT in inhibiting chronic CD8+ T cell-dependent responses.
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•Human and murine tumor-infiltrating CD8+ T cells express high levels of TIGIT•Antibody coblockade of TIGIT and PDL1 elicits tumor rejection in preclinical models•TIGIT selectively limits the effector function of chronically stimulated CD8+ T cells•TIGIT interacts with CD226 in cis and disrupts CD226 homodimerization
Checkpoint blockade has demonstrated success as a cancer immunotherapy strategy, but the limits of CTLA-4- and PD-1-blocking agents suggest the need for additional targets. Johnston et al. identify TIGIT as a coinhibitory receptor that critically limits antitumor CD8+ T cell-dependent immune responses
The mechanisms underlying specification of neuronal subtypes within the human nervous system are largely unknown. The blue (S), green (M), and red (L) cones of the retina enable high-acuity daytime ...and color vision. To determine the mechanism that controls S versus L/M fates, we studied the differentiation of human retinal organoids. Organoids and retinas have similar distributions, expression profiles, and morphologies of cone subtypes. S cones are specified first, followed by L/M cones, and thyroid hormone signaling controls this temporal switch. Dynamic expression of thyroid hormone-degrading and -activating proteins within the retina ensures low signaling early to specify S cones and high signaling late to produce L/M cones. This work establishes organoids as a model for determining mechanisms of human development with promising utility for therapeutics and vision repair.
Stochastic cell fate specification, in which a cell chooses between two or more fates with a set probability, diversifies cell subtypes in development. Although this is a vital process across ...species, a common mechanism for these cell fate decisions remains elusive. This review examines two well-characterized stochastic cell fate decisions to identify commonalities between their developmental programmes. In the fly eye, two subtypes of R7 photoreceptors are specified by the stochastic ON/OFF expression of a transcription factor,
. In the mouse olfactory system, olfactory sensory neurons (OSNs) randomly select to express one copy of an olfactory receptor (OR) gene out of a pool of 2800 alleles. Despite the differences in these sensory systems, both stochastic fate choices rely on the dynamic interplay between transcriptional priming, chromatin regulation and terminal gene expression. The coupling of transcription and chromatin modifications primes gene loci in undifferentiated neurons, enabling later expression during terminal differentiation. Here, we compare these mechanisms, examine broader implications for gene regulation during development and posit key challenges moving forward. This article is part of a discussion meeting issue 'Causes and consequences of stochastic processes in development and disease'.
The founders of sociomateriality argue that the difficulty of maintaining distinctions between material and social entities, increasingly encountered empirically, also necessitates a commitment to ...inseparability at the ontological level. Yet reservations have been voiced that this proposal is contrary to experience, incoherent, and of little practical use. While not denying the phenomenon, the critics insist that the ontological commitment to separated entities must be maintained. We show that Heidegger’s work in Being and Time (1927, 1962) provides a careful exploration of ontological inseparability that reveals it to be plausible, coherent, and useful. Although his terminology is alien, Heidegger’s analysis proceeds from everyday experiences to provide a plausible account of ontological inseparability. His work provides a coherent ontology that treats inseparability as fundamental, but also shows that our familiar dualist experience of the world, far from justifying ontological separation, is actually derivative. We demonstrate the usefulness of Heidegger’s concepts with a case. Instead of proceeding from a priori separated categories meaningful to the researcher, Heidegger’s concepts allow investigation of what IT “is” when involved in particular user worlds. We conclude that IS must engage with the “being of IT” if it wants to adequately deal with the increasing ubiquity of IT in practice.
The nature of follicular helper CD4
+ T (Tfh) cell differentiation remains controversial, including the minimal signals required for Tfh cell differentiation and the time at which Tfh cell ...differentiation occurs. Here we determine that Tfh cell development initiates immediately during dendritic cell (DC) priming in vivo. We demonstrate that inducible costimulator (ICOS) provides a critical early signal to induce the transcription factor Bcl6, and Bcl6 then induces CXCR5, the canonical feature of Tfh cells. Strikingly, a bifurcation between Tfh and effector Th cells was measurable by the second cell division of CD4
+ T cells, at day 2 after an acute viral infection: IL2Rα
int cells expressed Bcl6 and CXCR5 (Tfh cell program), whereas IL2Rα
hi cells exhibited strong Blimp1 expression that repressed Bcl6 (effector Th cell program). Virtually complete polarization between Bcl6
+ Tfh cells and Blimp1
+ effector Th cell populations developed by 72 hr, even without B cells. Tfh cells were subsequently lost in the absence of B cells, demonstrating a B cell requirement for maintenance of Bcl6 and Tfh cell commitment via sequential ICOS signals.
► DCs instruct Tfh cell differentiation ► Tfh cell differentiation is instructed by ICOS during priming and competes with IL-2 ► B cells are not required for Tfh cell commitment but are necessary for Tfh cell maintenance ► Tfh versus effector Th cell bifurcation can occur within two cell divisions in vivo
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