We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

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Upon entering the cerebral cortex sensory information spreads through six different horizontal neuronal layers that are interconnected by vertical axonal projections. It is believed that through these projections layers can influence each other’s response to sensory stimuli, yet the specific role played by each layer in cortical processing is still poorly understood. Here we show that layer 6 in the primary visual cortex of the mouse plays a crucial role in controlling the gain of visually evoked activity in neurons of the upper layers without, however, changing their tuning to orientation. This gain modulation results from the coordinated action of layer 6 projections to superficial layers and deep projections to the thalamus, with a substantial role of the former circuit. This study thus establishes L6 as a major mediator of cortical gain modulation and suggests it could be a node through which convergent inputs from several brain areas can regulate the earliest steps of cortical visual processing.

Summary The molecular mechanisms controlling the termination of cortical interneuron migration are unknown. Here we demonstrate that prior to synaptogenesis, migrating interneurons change their responsiveness to ambient GABA from a motogenic to a stop signal. We found that during migration into the cortex, ambient GABA and glutamate initially stimulate the motility of interneurons through both GABAA and AMPA/NMDA receptor activation. Once in the cortex, up-regulation of the potassium-chloride co-transporter KCC2 is both necessary and sufficient to reduce interneuron motility through its ability to reduce membrane potential upon GABAA receptor activation which decrease the frequency of spontaneous intracellular calcium transients initiated by L-type Voltage-Sensitive Calcium Channels (VSCC) activation. Our results suggest a novel mechanism whereby migrating interneurons determine the relative density of surrounding interneurons and principal cells through their ability to sense the combined extracellular levels of ambient glutamate and GABA once GABAA receptor activation becomes hyperpolarizing.

Summary In layer 6 (L6), a principal output layer of the mammalian cerebral cortex, a population of excitatory neurons defined by the NTSR1-Cre mouse line inhibit cortical responses to visual stimuli. Here we show that of the two major types of excitatory neurons existing in L6, the NTSR1-Cre line selectively targets those whose axon innervate both cortex and thalamus and not those whose axons remain within the cortex. These cortico-thalamic neurons mediate widespread inhibition across all cortical layers by recruiting fast-spiking inhibitory neurons whose cell-body resides in deep cortical layers yet whose axons arborize throughout all layers. This study reveals a circuit by which L6 modulates cortical activity and identifies an inhibitory neuron able to regulate the strength of cortical responses throughout cortical depth.