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T cells that recognize tumor antigens are crucial for mounting antitumor immune responses. Induction of antitumor T cells in immunogenic tumors depends on STING, the intracellular innate immune receptor for cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) and related cyclic dinucleotides (CDNs). However, the optimal way to leverage STING activation in nonimmunogenic tumors is still unclear. Here, we show that cGAMP delivery by intratumoral injection of virus-like particles (cGAMP-VLP) led to differentiation of circulating tumor-specific T cells, decreased tumor regulatory T cells (T regs ), and antitumoral responses that synergized with PD1 blockade. By contrast, intratumoral injection of the synthetic CDN ADU-S100 led to tumor necrosis and systemic T cell activation but simultaneously depleted immune cells from injected tumors and induced minimal priming of circulating tumor-specific T cells. The antitumor effects of cGAMP-VLP required type 1 conventional dendritic cells (cDC1), whereas ADU-S100 eliminated cDC1 from injected tumors. cGAMP-VLP preferentially targeted STING in dendritic cells at a 1000-fold smaller dose than ADU-S100. Subcutaneous administration of cGAMP-VLP showed synergy when combined with PD1 blockade or a tumor T reg -depleting antibody to elicit systemic tumor-specific T cells and antitumor activity, leading to complete and durable tumor eradication in the case of tumor T reg depletion. These findings show that cell targeting of STING stimulation shapes the antitumor T cell response and identify a therapeutic strategy to enhance T cell–targeted immunotherapy.

Increased number of circulating myeloid cells is a hallmark of most cancers, however it remains unclear how primary tumors impact on myelopoiesis. Here we show that non-metastatic breast tumors remotely instruct the fate of long-term hematopoietic stem cell (HSCLT) in the bone marrow. We found that HSCLT from tumor bearing mice acquire a myeloid bias persisting upon primary and secondary HSCLT transfer in lethally-irradiated tumor-free animals. By imaging the bone marrow HSC niche, we found that the tumor-bearing status is associated with increased physical interactions between mesenchymal stem/stromal cells (MSC) and HSCLT. Moreover, ex vivo co-culture experiments demonstrate that MSC isolated from tumor-bearing mice increase myeloid differentiation of HSCLT isolated from tumor free mice. In summary, our data reveal that breast cancer remotely promotes myelopoiesis at the earliest stages of hematopoietic differentiation in the BM mesenchymal niche.

Summary Dendritic cells (DCs) patrol tissues and transport antigens to lymph nodes to initiate adaptive immune responses. Within tissues, DCs constitute a complex cell population composed of distinct subsets that can exhibit different activation states and functions. How tissue-specific cues orchestrate DC diversification remains elusive. Here, we show that the small intestine included two pools of cDC2s originating from common pre-DC precursors: (1) lamina propria (LP) CD103+CD11b+ cDC2s that were mature-like proinflammatory cells and (2) intraepithelial cDC2s that exhibited an immature-like phenotype as well as tolerogenic properties. These phenotypes resulted from the action of food-derived retinoic acid (ATRA), which enhanced actomyosin contractility and promoted LP cDC2 transmigration into the epithelium. There, cDC2s were imprinted by environmental cues, including ATRA itself and the mucus component Muc2. Hence, by reaching distinct subtissular niches, DCs can exist as immature and mature cells within the same tissue, revealing an additional mechanism of DC functional diversification., Graphical abstract, Highlights • Epithelial colonization by gut cDC2s leads to their transcriptional reprograming • Unlike lamina propria cDC2s, intraepithelial cDC2s show an immature-like phenotype • Intraepithelial cDC2s trigger T cell hyporesponsiveness • The phenotype of intraepithelial cDC2s is imprinted by both retinoic acid and mucus, Gut cDC2s have been described to migrate into the epithelium, but whether this event modifies their phenotype is unknown. Rivera et al. show that upon epithelium colonization, cDC2s adopt an immature-like phenotype, revealing the existence of subtissular niches able to shape cDCs' fate and function.

Macrophage infiltration is a hallmark of solid cancers, and overall macrophage infiltration correlates with lower patient survival and resistance to therapy. Tumor-associated macrophages, however, are phenotypically and functionally heterogeneous. Specific subsets of tumor-associated macrophage might be endowed with distinct roles on cancer progression and antitumor immunity. Here, we identify a discrete population of FOLR2

Classical dendritic cells (cDCs) are mononuclear phagocytes of hematopoietic origin specialized in the induction and regulation of adaptive immunity. Initially defined by their unique T cell activation potential, it became quickly apparent that cDCs would be difficult to distinguish from other phagocyte lineages, by solely relying on marker-based approaches. Today, cDCs definition increasingly embed their unique ontogenetic features. A growing consensus defines cDCs on multiple criteria including: (1) dependency on the fms-like tyrosine kinase 3 ligand hematopoietic growth factor, (2) development from the common DC bone marrow progenitor, (3) constitutive expression of the transcription factor ZBTB46 and (4) the ability to induce, after adequate stimulation, the activation of naïve T lymphocytes. cDCs are a heterogeneous cell population that contains two main subsets, named type 1 and type 2 cDCs, arising from divergent ontogenetic pathways and populating multiple lymphoid and non-lymphoid tissues. Here, we present recent knowledge on the cellular and molecular pathways controlling the specification and commitment of cDC subsets from murine and human hematopoietic stem cells.

Classical dendritic cells (cDCs) are mononuclear phagocytes of hematopoietic origin specialized in the induction and regulation of adaptive immunity. Initially defined by their unique T cell activation potential, it became quickly apparent that cDCs would be difficult to distinguish from other phagocyte lineages, by solely relying on marker-based approaches. Today, cDCs definition increasingly embed their unique ontogenetic features. A growing consensus defines cDCs on multiple criteria including: (1) dependency on the fms-like tyrosine kinase 3 ligand hematopoietic growth factor, (2) development from the common DC bone marrow progenitor, (3) constitutive expression of the transcription factor ZBTB46 and (4) the ability to induce, after adequate stimulation, the activation of naive T lymphocytes. cDCs are a heterogeneous cell population that contains two main subsets, named type 1 and type 2 cDCs, arising from divergent ontogenetic pathways and populating multiple lymphoid and non-lymphoid tissues. Here, we present recent knowledge on the cellular and molecular pathways controlling the specification and commitment of cDC subsets from murine and human hematopoietic stem cells.