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Dendritic cells (DCs) are specialized antigen-presenting cells that are present at low abundance in the circulation and tissues; they serve as crucial immune sentinels by continually sampling their environment, migrating to secondary lymphoid organs and shaping adaptive immune responses through antigen presentation. Owing to their ability to orchestrate tolerogenic or immunogenic responses to a specific antigen, DCs have a pivotal role in antitumour immunity and the response to immune checkpoint blockade and other immunotherapeutic approaches. The multifaceted functions of DCs are acquired through a complex, multistage process called maturation. Although the role of inflammatory triggers in driving DC maturation was established decades ago, less is known about DC maturation in non-inflammatory contexts, such as during homeostasis and in cancer. The advent of single-cell technologies has enabled an unbiased, high-dimensional characterization of various DC states, including mature DCs. This approach has clarified the molecular programmes associated with DC maturation and also revealed how cancers exploit these pathways to subvert immune surveillance. In this Review, we discuss the mechanisms by which cancer disrupts DC maturation and highlight emerging therapeutic opportunities to modulate DC states. These insights could inform the development of DC-centric immunotherapies, expanding the arsenal of strategies to enhance antitumour immunity. Dendritic cells (DCs) shape the adaptive immune response to peripheral tissue antigens and, as such, are crucial for mounting an effective antitumour immune response in cancer. This Review outlines the molecular basis of DC maturation, highlights the mechanisms through which cancer impairs DC maturation and considers the potential for DC-focused cancer immunotherapeutics.

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.

A preprint by Mayer et al. reveals the role played by environmental IL-13 in shaping the balance of type 2 dendritic cell molecular composition in the dermis.

The recently discovered histone post-translational modification crotonylation connects cellular metabolism to gene regulation. Its regulation and tissue-specific functions are poorly understood. We characterize histone crotonylation in intestinal epithelia and find that histone H3 crotonylation at lysine 18 is a surprisingly abundant modification in the small intestine crypt and colon, and is linked to gene regulation. We show that this modification is highly dynamic and regulated during the cell cycle. We identify class I histone deacetylases, HDAC1, HDAC2, and HDAC3, as major executors of histone decrotonylation. We show that known HDAC inhibitors, including the gut microbiota-derived butyrate, affect histone decrotonylation. Consistent with this, we find that depletion of the gut microbiota leads to a global change in histone crotonylation in the colon. Our results suggest that histone crotonylation connects chromatin to the gut microbiota, at least in part, via short-chain fatty acids and HDACs. Histone post-translational modifications are known key regulators of gene expression. Here, the authors characterize histone crotonylation at histone H3 lysine 18 in intestinal epithelia and find that it is a highly dynamic cell cycle regulated mark under the regulation of the HDAC deacetylases.

Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13 + CH25H + IL-21 + PD-1 + CD4 + T helper cells (“CXCL13 + T H ”) and Granzyme K + PD-1 + effector-like CD8 + T cells, whereas terminally exhausted CD39 hi TOX hi PD-1 hi CD8 + T cells dominated in nonresponders. CD4 + and CD8 + T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1 + TCF-1 + (Progenitor-exhausted) CD8 + T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8 + T cell differentiation occurs upon ICB. We found that these Progenitor CD8 + T cells interact with CXCL13 + T H within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or “mregDC”. These results suggest that discrete intratumoral niches that include mregDC and CXCL13 + T H control the differentiation of tumor-specific Progenitor exhasuted CD8 + T cells following ICB. Response to anti-PD-1 in patients with hepatocellular carcinoma is associated with clonal expansion of intratumoral CXCL13 + CD4 + helper T cells and effector-like CD8 + T cells, and local dendritic cells enriched in expression of maturation and regulatory molecules help facilitate CD8 + T cell differentiation.

A Correction to this paper has been published: https://doi.org/10.1038/s41577-021-00555-6.

Myeloid cells are known to suppress antitumour immunity 1 . However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab 2 – 5 given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450 ). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site. Single-cell transcriptomics studies on human and mouse non-small cell lung cancer and conditional knockout mouse models show that IL-4 from bone marrow basophils drives the development of granulocyte-monocyte progenitors to myeloid cells that suppress antitumour immunity.

Maturation of conventional dendritic cells (cDCs) is crucial for maintaining tolerogenic safeguards against auto-immunity and for promoting immunogenic responses to pathogens and cancer. The subcellular mechanism for cDC maturation remains poorly defined. We show that cDCs mature by leveraging an internal reservoir of cholesterol (harnessed from extracellular cell debris and generated by de novo synthesis) to assemble lipid nanodomains on cell surfaces of maturing cDCs, enhance expression of maturation markers and stabilize immune receptor signaling. This process is dependent on cholesterol transport through Niemann–Pick disease type C1 (NPC1) and mediates homeostatic and Toll-like receptor (TLR)-induced maturation. Importantly, we identified the receptor tyrosine kinase AXL as a regulator of the NPC1-dependent construction of lipid nanodomains. Deleting AXL from cDCs enhances their maturation, thus improving anti-tumor immunity. Altogether, our study presents new insights into cholesterol mobilization as a fundamental basis for cDC maturation and highlights AXL as a therapeutic target for modulating cDCs. To mature, dendritic cells collect and synthesize cholesterol to construct lipid nanodomains on their membranes. Obstructing this process impairs their ability to prime T cells.

Background How intestinal epithelial cells interact with the microbiota and how this is regulated at the gene expression level are critical questions. Smarcad1 is a conserved chromatin remodeling factor with a poorly understood tissue function. As this factor is highly expressed in the stem and proliferative zones of the intestinal epithelium, we explore its role in this tissue. Results Specific deletion of Smarcad1 in the mouse intestinal epithelium leads to colitis resistance and substantial changes in gene expression, including a striking increase of expression of several genes linked to innate immunity. Absence of Smarcad1 leads to changes in chromatin accessibility and significant changes in histone H3K9me3 over many sites, including genes that are differentially regulated upon Smarcad1 deletion. We identify candidate members of the gut microbiome that elicit a Smarcad1-dependent colitis response, including members of the poorly understood TM7 phylum. Conclusions Our study sheds light onto the role of the chromatin remodeling machinery in intestinal epithelial cells in the colitis response and shows how a highly conserved chromatin remodeling factor has a distinct role in anti-microbial defense. This work highlights the importance of the intestinal epithelium in the colitis response and the potential of microbial species as pharmacological and probiotic targets in the context of inflammatory diseases.

Despite being implicated in non-lymphoid tissues, non-recirculating T cells may also exist in secondary lymphoid organs (SLO). However, a detailed characterization of this lymphoid-resident T cell pool has not yet been done. Here we show that a substantial proportion of CD4 regulatory (Treg) and memory (Tmem) cells establish long-term residence in the SLOs of specific pathogen-free mice. Of these SLOs, only T cell residence within Peyer’s patches is affected by microbiota. Resident CD4 Treg and CD4 Tmem cells from lymph nodes and non-lymphoid tissues share many phenotypic and functional characteristics. The percentage of resident T cells in SLOs increases considerably with age, with S1PR1 downregulation possibly contributing to this altered homeostasis. Our results thus show that T cell residence is not only a hallmark of non-lymphoid tissues, but can be extended to secondary lymphoid organs. Non-circulating, tissue-resident T cells have been reported for non-lymphoid organs, but their characterization and regulation in secondary lymphoid organs (SLO) are still lacking. Here the authors show that age and microbiota both exert SLO-specific effects for the various tissue-resident T cell subsets.