Dendritic cells (DCs) are essential for the establishment of immune responses against pathogens and tumour cells, and thus have great potential as tools for vaccination and cancer immunotherapy trials. Experimental evidence has led to a dual DC differentiation model, which involves the existence of both myeloid- and lymphoid-derived DCs. But this concept has been challenged by recent reports demonstrating that both CD8- and CD8+ DCs, considered in mice as archetypes of myeloid and lymphoid DCs respectively, can be generated from either lymphoid or myeloid progenitors. The issue of DC physiological derivation therefore remains an open question. Here we report the characterization of a DC-committed precursor population, which has the capacity to generate all the DC subpopulations present in mouse lymphoid organs---including CD8- and CD8+ DCs, as well as the B220+ DC subset---but which is devoid of myeloid or lymphoid differentiation potential. These data support an alternative model of DC development, in which there is an independent, common DC differentiation pathway.
The tumor immune microenvironment is a main contributor to cancer progression and a promising therapeutic target for oncology. However, immune microenvironments vary profoundly between patients, and biomarkers for prognosis and treatment response lack precision. A comprehensive compendium of tumor immune cells is required to pinpoint predictive cellular states and their spatial localization. We generated a single-cell tumor immune atlas, jointly analyzing published data sets of >500,000 cells from 217 patients and 13 cancer types, providing the basis for a patient stratification based on immune cell compositions. Projecting immune cells from external tumors onto the atlas facilitated an automated cell annotation system. To enable in situ mapping of immune populations for digital pathology, we applied SPOTlight, combining single-cell and spatial transcriptomics data and identifying colocalization patterns of immune, stromal, and cancer cells in tumor sections. We expect the tumor immune cell atlas, together with our versatile toolbox for precision oncology, to advance currently applied stratification approaches for prognosis and immunotherapy.
Brain metastases are the most common tumor of the brain with a dismal prognosis. A fraction of patients with brain metastasis benefit from treatment with immune checkpoint inhibitors (ICI) and the degree and phenotype of the immune cell infiltration has been used to predict response to ICI. However, the anatomical location of brain lesions limits access to tumor material to characterize the immune phenotype. Here, we characterize immune cells present in brain lesions and matched cerebrospinal fluid (CSF) using single-cell RNA sequencing combined with T cell receptor genotyping. Tumor immune infiltration and specifically CD8+ T cell infiltration can be discerned through the analysis of the CSF. Consistently, identical T cell receptor clonotypes are detected in brain lesions and CSF, confirming cell exchange between these compartments. The analysis of immune cells of the CSF can provide a non-invasive alternative to predict the response to ICI, as well as identify the T cell receptor clonotypes present in brain metastasis.
IntroductionDendritic cells (DCs) play a central role in the immune system due to their main function as initiators and regulators of antigenspecific antiviral T-cell responses and in the pathogenesis of a variety of viruses, such as human immunodeficiency virus (HIV), cytomegalovirus, measles virus, herpes virus, influenza virus, and respiratory syncytial virus. 1 However, little is known about the subpopulations of DCs involved in antiviral responses, the kinetics of the variations of DC subpopulations, and, importantly, the mechanisms of recruitment of DCs to the lymph nodes (LNs) during inflammatory responses driven by viral infections. On the other hand, despite the available information dealing with the phenotype and function of the 2 main mouse DC subsets, namely, CD8 Ϫ and CD8 ϩ DCs, their involvement in antiviral immune responses in vivo as well as their functional relationships and origin remain largely unknown.Over the last years CD8 Ϫ and CD8 ϩ DCs have been ascribed to the myeloid and lymphoid lineages, respectively, and consequently considered as independent DC categories. 1 However, more recently 2 reports from our group and Dr Weissman's laboratory (Stanford University) have described the generation of both CD8 Ϫ and CD8 ϩ DCs from a common lymphoid precursor 2 or from either myeloidor lymphoid-committed precursors. 3 These results suggest that in fact CD8 Ϫ and CD8 ϩ DCs might not represent independent cell types, and in this sense we have previously reported that migrationor CD40L ligation-induced Langerhans cell (LC) maturation involved CD8 up-regulation. 4,5 In these reports, which have been confirmed by a recent article by Merad et al, 6 we showed that the LN-restricted CD8 int DC population derived from LCs. 4,5 On the basis of these previous data on LN DCs and using the dramatic changes occurring in the draining popliteal LNs (PO-LNs) after infection by the Swiss (SW) strain of the mouse mammary tumor virus (MMTV), 7 we have extensively analyzed the mechanisms of DC recruitment during the inflammatory responses induced by a viral infection as well as the relationships between the different DC subsets involved. The results presented here indicate that MMTV(SW) induces a strong migration of blood-borne CD8 Ϫ DCs to the PO-LNs via high endothelial venules (HEVs), providing direct evidence of DC recruitment to the LNs during an in vivo viral infection-driven inflammatory process. Moreover, our data strongly suggest that LN CD8 ϩ DCs originate as the result of CD8 up-regulation by LN CD8 Ϫ DCs, supporting the view that these subsets represent different physiologic states of the same DC population. Finally, the fact that DCs become infected by MMTV(SW) suggest their participation in the immune response against this virus. Materials and methods Experimental infection with MMTV(SW)The MMTV(SW) was purified from milk and titered as described previously. 8 Eight-to 10-week-old BALB/c mice were given a 10-L injection Supported by the European Commission (grant no. QLRT-1999-00276) For personal use on...
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