Explore the vast range of titles available.

Dendritic cells (DCs) are endowed with a unique potency to prime T cells, as well as to orchestrate their expansion, functional polarization and effector activity in non-lymphoid tissues or in their draining lymph nodes. The concept of harnessing DC immunogenicity to induce protective responses in cancer patients was put forward about 25 years ago and has led to a multitude of DC-based vaccine trials. However, until very recently, objective clinical responses were below expectations. Conventional type 1 DCs (cDC1) excel in the activation of cytotoxic lymphocytes including CD8 T cells (CTLs), natural killer (NK) cells, and NKT cells, which are all critical effector cell types in antitumor immunity. Efforts to investigate whether cDC1 might orchestrate immune defenses against cancer are ongoing, thanks to the recent blossoming of tools allowing their manipulation . Here we are reporting on these studies. We discuss the mouse models used to genetically deplete or manipulate cDC1, and their main caveats. We present current knowledge on the role of cDC1 in the spontaneous immune rejection of tumors engrafted in syngeneic mouse recipients, as a surrogate model to cancer immunosurveillance, and how this process is promoted by type I interferon (IFN-I) effects on cDC1. We also discuss cDC1 implication in promoting the protective effects of immunotherapies in mouse preclinical models, especially for adoptive cell transfer (ACT) and immune checkpoint blockers (ICB). We elaborate on how to improve this process by reprogramming of certain cDC1 functions with off-the-shelf compounds. We also summarize and discuss basic research and clinical data supporting the hypothesis that the protective antitumor functions of cDC1 inferred from mouse preclinical models are conserved in humans. This analysis supports potential applicability to cancer patients of the cDC1-targeting adjuvant immunotherapies showing promising results in mouse models. Nonetheless, further investigations on cDC1 and their implications in anti-cancer mechanisms are needed to determine whether they are the missing key that will ultimately help switching cold tumors into therapeutically responsive hot tumors, and how precisely they mediate their protective effects.

Infected cells detect viruses through a variety of receptors that initiate cell-intrinsic innate defense responses. Cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) synthase (cGAS) is a cytosolic sensor for many DNA viruses and HIV-1. In response to cytosolic viral DNA, cGAS synthesizes the second messenger 2′3′-cyclic GMP-AMP (cGAMP), which activates antiviral signaling pathways. We show that in cells producing virus, cGAS-synthesized cGAMP can be packaged in viral particles and extracellular vesicles. Viral particles efficiently delivered cGAMP to target cells. cGAMP transfer by viral particles to dendritic cells activated innate immunity and antiviral defenses. Finally, we show that cell-free murine cytomegalovirus and Modified Vaccinia Ankara virus contained cGAMP. Thus, transfer of cGAMP by viruses may represent a defense mechanism to propagate immune responses to uninfected target cells.

Plasmacytoid dendritic cells (pDCs) are a major source of type I interferon (IFN-I). What other functions pDCs exert in vivo during viral infections is controversial, and more studies are needed to understand their orchestration. In the present study, we characterize in depth and link pDC activation states in animals infected by mouse cytomegalovirus by combining Ifnb1 reporter mice with flow cytometry, single-cell RNA sequencing, confocal microscopy and a cognate CD4 T cell activation assay. We show that IFN-I production and T cell activation were performed by the same pDC, but these occurred sequentially in time and in different micro-anatomical locations. In addition, we show that pDC commitment to IFN-I production was marked early on by their downregulation of leukemia inhibitory factor receptor and was promoted by cell-intrinsic tumor necrosis factor signaling. We propose a new model for how individual pDCs are endowed to exert different functions in vivo during a viral infection, in a manner tightly orchestrated in time and space. Plasmacytoid dendritic cells (pDCs) are a major source of type I interferon (IFN-I). Dalod and colleagues show that IFN-I production and T cell activation were performed by the same pDC, but these occurred sequentially and in different micro-anatomical locations during virus infection.

Cross-presentation by type 1 DCs (cDC1) is critical to induce and sustain antitumoral CD8 T cell responses to model antigens, in various tumor settings. However, the impact of cross-presenting cDC1 and the potential of DC-based therapies in tumors carrying varied levels of bona-fide neoantigens (neoAgs) remain unclear. Here we develop a hypermutated model of non-small cell lung cancer in female mice, encoding genuine MHC-I neoepitopes to study neoAgs-specific CD8 T cell responses in spontaneous settings and upon Flt3L + αCD40 (DC-therapy). We find that cDC1 are required to generate broad CD8 responses against a range of diverse neoAgs. DC-therapy promotes immunogenicity of weaker neoAgs and strongly inhibits the growth of high tumor-mutational burden (TMB) tumors. In contrast, low TMB tumors respond poorly to DC-therapy, generating mild CD8 T cell responses that are not sufficient to block progression. scRNA transcriptional analysis, immune profiling and functional assays unveil the changes induced by DC-therapy in lung tissues, which comprise accumulation of cDC1 with increased immunostimulatory properties and less exhausted effector CD8 T cells. We conclude that boosting cDC1 activity is critical to broaden the diversity of anti-tumoral CD8 T cell responses and to leverage neoAgs content for therapeutic advantage. Response to immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC) remains suboptimal, even for tumors with elevated tumor mutational burden. Here the authors generate a model of NSCLC with enhanced mutational load, showing that, while still resistant to ICIs, hypermutated tumors become sensitive to dendritic cell-targeted therapy.

Cytotoxic CD4 (CD4CTX) T cells are emerging as an important component of antiviral and antitumor immunity, but the molecular basis of their development remains poorly understood. In the context of human cytomegalovirus infection, a significant proportion of CD4 T cells displays cytotoxic functions. We observed that the transcriptional program of these cells was enriched in CD8 T cell lineage genes despite the absence of ThPOK downregulation. We further show that establishment of CD4CTX-specific transcriptional and epigenetic programs occurred in a stepwise fashion along the Th1-differentiation pathway. In vitro, prolonged activation of naive CD4 T cells in presence of Th1 polarizing cytokines led to the acquisition of perforin-dependent cytotoxic activity. This process was dependent on the Th1 transcription factor Runx3 and was limited by the sustained expression of ThPOK. This work elucidates the molecular program of human CD4CTX T cells and identifies potential targets for immunotherapy against viral infections and cancer.

Currently three bona fide dendritic cell (DC) types are distinguished in human blood. Herein we focus on type 2 DCs (DC2s) and compare the three defining markers CD1c, CD172, and CD301. When using CD1c to define DC2s, a CD14 and a CD14 subset can be detected. The CD14 subset shares features with monocytes, and this includes substantially higher expression levels for CD64, CD115, CD163, and S100A8/9. We review the current knowledge of these CD1c CD14 cells as compared to the CD1c CD14 cells with respect to phenotype, function, transcriptomics, and ontogeny. Here, we discuss informative mutations, which suggest that two populations have different developmental requirements. In addition, we cover subsets of CD11c CD8 DC2s in the mouse, where CLEC12A ESAM cells, as compared to the CLEC12A ESAM subset, also express higher levels of monocyte-associated markers CD14, CD3, and CD115. Finally, we summarize, for both man and mouse, the data on lower antigen presentation and higher cytokine production in the monocyte-marker expressing DC2 subset, which demonstrate that the DC2 subsets are also functionally distinct.

Tumor infiltration by XCR1⁺ conventional dendritic cells (cDC1) correlates strongly with favorable prognosis and improved responses to immunotherapy. Yet, tumor-driven immunosuppressive programs restrict efficient cDC1 recruitment, highlighting the need for strategies to increase cDC1 access to the tumor microenvironment. Here, we establish a proof-of-concept cell-based immunotherapy that enhances the infiltration of circulating cDC1 progenitors and supports their local expansion. Intratumoral engraftment of autologous mesenchymal stromal cells engineered to express membrane bound FLT3L promotes cDC1 recruitment when combined with poly(I:C). We identify poly(I:C)-induced CXCL9 and CCL5 as essential chemokines controlling intratumoral cDC1 infiltration. Stromal cell–mediated local delivery of FLT3L together with CXCL9 and CCL5 is sufficient to enhance cDC1 infiltration in mice or humanized mice settings. Finally, this approach activates antitumor immunity and partially overcomes resistance to immune checkpoint blockade. Collectively, our data support the therapeutic potential of expanding intratumoral cDC1s through local and sustained delivery of FLT3L, CXCL9, and CCL5. XCR1+ type 1 conventional DCs (cDC1s) are crucial to mount anti-tumor immune responses, however their infiltration within tumours is often limited. Here the authors show that cDC1 infiltration could be expanded by intratumoral delivery of mesenchymal stromal cells engineered to express the membrane bound form of FLT3L in combination with poly(I:C) or CXCL9 and CCL5, improving anti-tumor immunity in preclinical models.

Immune response against pathogens is a tightly regulated process that must ensure microbial control while preserving integrity of the infected organs. Tuberculosis (TB) is a paramount example of a chronic infection in which antimicrobial immunity is protective in the vast majority of infected individuals but can become detrimental if not finely tuned. Here, we report that C-type lectin dendritic cell (DC) immunoreceptor (DCIR), a key component in DC homeostasis, is required to modulate lung inflammation and bacterial burden in TB. DCIR is abundantly expressed in pulmonary lesions in Mycobacterium tuberculosis-infected nonhuman primates during both latent and active disease. In mice, we found that DCIR deficiency impairs STAT1-mediated type I IFN signaling in DCs, leading to increased production of IL-12 and increased differentiation of T lymphocytes toward Th1 during infection. As a consequence, DCIR-deficient mice control M. tuberculosis better than WT animals but also develop more inflammation characterized by an increased production of TNF and inducible NOS (iNOS) in the lungs. Altogether, our results reveal a pathway by which a C-type lectin modulates the equilibrium between infection-driven inflammation and pathogen’s control through sustaining type I IFN signaling in DCs.

Therapies reconstituting autologous antiviral immunocompetence may represent an important prophylaxis and treatment for immunosuppressed individuals. Following hematopoietic cell transplantation (HCT), patients are susceptible to Herpesviridae including cytomegalovirus (CMV). We show in a murine model of HCT that macrophage colony‐stimulating factor (M‐CSF) promoted rapid antiviral activity and protection from viremia caused by murine CMV. M‐CSF given at transplantation stimulated sequential myeloid and natural killer (NK) cell differentiation culminating in increased NK cell numbers, production of granzyme B and interferon‐γ. This depended upon M‐CSF‐induced myelopoiesis leading to IL15Rα‐mediated presentation of IL‐15 on monocytes, augmented by type I interferons from plasmacytoid dendritic cells. Demonstrating relevance to human HCT, M‐CSF induced myelomonocytic IL15Rα expression and numbers of functional NK cells in G‐CSF‐mobilized hematopoietic stem and progenitor cells. Together, M‐CSF‐induced myelopoiesis triggered an integrated differentiation of myeloid and NK cells to protect HCT recipients from CMV. Thus, our results identify a rationale for the therapeutic use of M‐CSF to rapidly reconstitute antiviral activity in immunocompromised individuals, which may provide a general paradigm to boost innate antiviral immunocompetence using host‐directed therapies. Synopsis Herpesviridae like CMV are a major cause of morbidity and mortality in patients after HCT. Therapies reconstituting the host's antiviral immunocompetence for prophylaxis and treatment are an unmet medical need since licensed therapies are either insufficiently effective or have severe side effects. M‐CSF protects from lethal murine CMV viremia during leukopenia following hematopoietic cell transplantation, a vulnerable period of immunosuppression, by rapidly reconstituting donor hematopoietic stem and progenitor cells. M‐CSF stimulates a coordinated myeloid and NK cell differentiation program resulting in increased NK cell numbers and activity, which depends on M‐CSF‐induced myelopoiesis generating IL‐15‐producing monocytes and I‐IFN‐producing pDCs. No impairment of long‐term hematopoietic stem cell engraftment or acute graft‐versus‐host‐disease after M‐CSF treatment was observed. In G‐CSF‐mobilized human PBMCs M‐CSF also stimulates monopoiesis, IL15Rα expression in monocytes and functional NK cell differentiation. M‐CSF could provide a general host‐directed antiviral cytokine therapy, to complement pathogen‐directed antiviral therapies in immunosuppressed conditions beyond HCT, such as post‐chemotherapy leukopenia or septicemia. Graphical Abstract Herpesviridae like CMV are a major cause of morbidity and mortality in patients after HCT. Therapies reconstituting the host's antiviral immunocompetence for prophylaxis and treatment are an unmet medical need since licensed therapies are either insufficiently effective or have severe side effects.