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B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.

Human society is dependent on nature1,2, but whether our ecological foundations are at risk remains unknown in the absence of systematic monitoring of species’ populations3. Knowledge of species fluctuations is particularly inadequate in the marine realm4. Here we assess the population trends of 1,057 common shallow reef species from multiple phyla at 1,636 sites around Australia over the past decade. Most populations decreased over this period, including many tropical fishes, temperate invertebrates (particularly echinoderms) and southwestern Australian macroalgae, whereas coral populations remained relatively stable. Population declines typically followed heatwave years, when local water temperatures were more than 0.5 °C above temperatures in 2008. Following heatwaves5,6, species abundances generally tended to decline near warm range edges, and increase near cool range edges. More than 30% of shallow invertebrate species in cool latitudes exhibited high extinction risk, with rapidly declining populations trapped by deep ocean barriers, preventing poleward retreat as temperatures rise. Greater conservation effort is needed to safeguard temperate marine ecosystems, which are disproportionately threatened and include species with deep evolutionary roots. Fundamental among such efforts, and broader societal needs to efficiently adapt to interacting anthropogenic and natural pressures, is greatly expanded monitoring of species’ population trends7,8.

Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses1. The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset2–5. Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed.

Letter to the Editor

The analysis of T-cell antigens in long-term survivors of pancreatic ductal adenocarcinoma suggests that neoantigen immunogenicity and quality, not purely quantity, correlate with survival.

The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium—an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5+intestinal stem cells (ISCs). R-spondin ligands (RSPO1–RSPO4) engage distinct LGR4–LGR6, RNF43 and ZNRF3 receptor classes, markedly potentiate canonical Wnt/β-catenin signalling, and induce intestinal organoid growth in vitro and Lgr5+ISCs in vivo. However, the interchangeability, functional cooperation and relative contributions of Wnt versus RSPO ligands to in vivo canonical Wnt signalling and ISC biology remain unknown. Here we identify the functional roles of Wnt and RSPO ligands in the intestinal crypt stem-cell niche. We show that the default fate of Lgr5+ISCs is to differentiate, unless both RSPO and Wnt ligands are present. However, gain-of-function studies using RSPO ligands and a new non-lipidated Wnt analogue reveal that these ligands have qualitatively distinct, non-interchangeable roles in ISCs. Wnt proteins are unable to induce Lgr5+ISC self-renewal, but instead confer a basal competency by maintaining RSPO receptor expression that enables RSPO ligands to actively drive and specify the extent of stem-cell expansion. This functionally non-equivalent yet cooperative interaction between Wnt and RSPO ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precise control of tissue regeneration.

The brain’s ability to associate different stimuli is vital for long-term memory, but how neural ensembles encode associative memories is unknown. Here we studied how cell ensembles in the basal and lateral amygdala encode associations between conditioned and unconditioned stimuli (CS and US, respectively). Using a miniature fluorescence microscope, we tracked the Ca2+dynamics of ensembles of amygdalar neurons during fear learning and extinction over 6 days in behaving mice. Fear conditioning induced both up- and down-regulation of individual cells’ CS-evoked responses. This bi-directional plasticity mainly occurred after conditioning, and reshaped the neural ensemble representation of the CS to become more similar to the US representation. During extinction training with repetitive CS presentations, the CS representation became more distinctive without reverting to its original form. Throughout the experiments, the strength of the ensemble-encoded CS–US association predicted the level of behavioural conditioning in each mouse. These findings support a supervised learning model in which activation of the US representation guides the transformation of the CS representation.

How does an animal know where it is when it stops moving? Hippocampal place cells fire at discrete locations as subjects traverse space, thereby providing an explicit neural code for current location during locomotion. In contrast, during awake immobility, the hippocampus is thought to be dominated by neural firing representing past and possible future experience. The question of whether and how the hippocampus constructs a representation of current location in the absence of locomotion has been unresolved. Here we report that a distinct population of hippocampal neurons, located in the CA2 subregion, signals current location during immobility, and does so in association with a previously unidentified hippocampus-wide network pattern. In addition, signalling of location persists into brief periods of desynchronization prevalent in slow-wave sleep. The hippocampus thus generates a distinct representation of current location during immobility, pointing to mnemonic processing specific to experience occurring in the absence of locomotion.

Two strains of White Leghorn chickens designated as R and S have been developed from common parentage at this station1. When chickens of these two strains were injected intramuscularly with 3 mg mercury as phenyl-mercuric acetate (PMA) or mercuric chloride/kg/body-wt., 2–4 times more mercury was retained by the livers and kidneys of the R strain chickens than was retained by the same organs from the S strain chickens2,3. Lillis et al.4reported a similar differential retention when chickens from these strains were injected with 9.1 mg copper as cupric acetate/kg/body-wt.

FOR any of a wide variety of pairs of n-alkanes it is known1,2that at 20° C the heat of mixing is positive. Until about two years ago it was assumed on the basis of the measurements by van der Waals and Hermans1that as the temperature was increased the heat of mixing of any pair decreased, markedly at first, but remained positive. Then we published2some measurements of the heat of mixing of n-hexane + n-hexadecane at 20°, 30°, 40°, and 50° C. At 20° C our measurements were in fair agreement with those of van der Waals and Hermans. The temperature-dependence of our measurements was, however, strikingly different from that found by them for other pairs. By extrapolation of our results3and on theoretical grounds4we predicted that for n-hexane + n-hexadecane the heat of mixing should change sign at about 64° C and become negative at higher temperatures. That prediction became the subject of a wager (of a good dinner) between members of the ‘Liquids Club’ at the Shell Laboratory in Amsterdam and one of us (M.L.M.) in Reading, and has recently been publicly challenged on theoretical grounds by Holleman and Hijmans5. We have now used a modified version of our calorimeter6to make a few measurements on equimolar mixtures of n-hexane + n-hexadecane at 40°, 75°, and 100° C. The results of these new measurements are shown plotted against temperature in Fig. 1 together with the results of all the previous measurements made at more than one temperatur.

IT now seems clear that preparations of infective ‘ribonucleic acid’ can be obtained from crude preparations of many animal viruses, although Colter et al. have reported failure with Bunyamwera virus preparations1. The technique used in most cases is similar to the treatment introduced by Gierer and Schramm2, namely, exposure of the virus preparation to concentrated phenol. Recognition that the infectivity of the product of phenol treatment is due to a component other than intact virus is based on such criteria as susceptibility to ribonucleases, stability in different media and rate of sedimentation in the ultracentrifuge1,2.

RECENT work by Reeves et al.1has shown that, under certain conditions, electronically excited molecules of O2, N2, NO, etc., can be formed by the heterogeneous recombination of free atoms on a metal surface. In these experiments light emission was observed from the gas just above the metal surface, showing that the molecules formed were desorbed in an excited electronic state. This evidence, and data on the kinetics of heterogeneous recombination2,3, suggest that this desorption process is very rapid and that the molecules liberated may have excess kinetic energy. In this communication we report on an unsuccessful attempt to obtain evidence for such excess kinetic energy, by comparing the pressure exerted by a mixture of atoms and molecules on a surface where recombination takes place with the pressure on a surface where recombination is negligible.

NEONATAL animals and animals given large doses of whole-body X-irradiation are immunologically similar in two important respects: both are very poor producers of antibody, but both become satisfactory producers of antibody after several weeks, presuming that the X-irradiated animals survive. It is well established that during normal maturation animals go through a stage during which they may be rendered immunologically tolerant of certain antigens1, and it seemed of considerable interest to determine whether, following severe X-ray damage, a similar stage occurred during which tolerance could be induced by appropriate antigenic stimulation. As X-ray damage is followed by rapid proliferation and differentiation of mesenchymal cells, be they the animal's own or bone-marrow cells grafted from a normal donor, it seemed possible that there might be a stage during which potential antibody-producing cells could be modified by contact with antigen and rendered immunologically tolerant.

IT has been shown1that when preparations of MEF1(type II) polio-virus (P. hominis) are exposed to heat at 50° C., there is a marked reduction in the rate of inactivation as the exposure time is increased (see Fig. 1). Bodian et al.2have suggested that such a phenomenon occurring during the inactivation of polio-virus with formaldehyde may be due to (1) protection of some virus particles by aggregation, or (2) the presence of inherently resistant particles, and concluded that there was no evidence to support the latter possibility. Since either of these possibilities may explain our results with heat as the inactivating agent, they formed the basis of further experiments.