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Dendritic cells (DCs) play a central role in the regulation of the balance between CD8 T cell immunity vs. tolerance to tumor antigens. Cross-priming, a process which DCs activate CD8 T cells by cross-presenting exogenous antigens, plays a critical role in generating anti-tumor CD8 T cell immunity. However, there are compelling evidences now that the tumor microenvironment (TME)-mediated suppression and modulation of tumor-infiltrated DCs (TIDCs) impair their function in initiating potent anti-tumor immunity and even promote tumor progression. Thus, DC-mediated cross-presentation of tumor antigens in tumor-bearing hosts often induces T cell tolerance instead of immunity. As tumor-induced immunosuppression remains one of the major hurdles for cancer immunotherapy, understanding how DCs regulate anti-tumor CD8 T cell immunity in particular within TME has been under intensive investigation. Recent reports on the Batf3-dependent type 1 conventional DCs (cDC1s) in anti-tumor immunity have greatly advanced our understanding on the interplay of DCs and CD8 T cells in the TME, highlighted by the critical role of CD103 cDC1s in the cross-priming of tumor antigen-specific CD8 T cells. In this review, we will discuss recent advances in anti-tumor CD8 T cell cross-priming by CD103 cDC1s in TME, and share perspective on future directions including therapeutic applications and memory CD8 T cell responses.

Although plasmacytoid dendritic cells (pDCs) have been shown to play a critical role in generating viral immunity and promoting tolerance to suppress antitumor immunity, whether and how pDCs cross-prime CD8 T cells in vivo remain controversial. Using a pDC-targeted vaccine model to deliver antigens specifically to pDCs, we have demonstrated that pDC-targeted vaccination led to strong cross-priming and durable CD8 T cell immunity. Surprisingly, cross-presenting pDCs required conventional DCs (cDCs) to achieve cross-priming in vivo by transferring antigens to cDCs. Taking advantage of an in vitro system where only pDCs had access to antigens, we further demonstrated that cross-presenting pDCs were unable to efficiently prime CD8 T cells by themselves, but conferred antigen-naive cDCs the capability of cross-priming CD8 T cells by transferring antigens to cDCs. Although both cDC1s and cDC2s exhibited similar efficiency in acquiring antigens from pDCs, cDC1s but not cDC2s were required for cross-priming upon pDC-targeted vaccination, suggesting that cDC1s played a critical role in pDC-mediated cross-priming independent of their function in antigen presentation. Antigen transfer from pDCs to cDCs was mediated by previously unreported pDC-derived exosomes (pDCexos), that were also produced by pDCs under various conditions. Importantly, all these pDCexos primed naive antigen-specific CD8 T cells only in the presence of bystander cDCs, similarly to cross-presenting pDCs, thus identifying pDCexo-mediated antigen transfer to cDCs as a mechanism for pDCs to achieve cross-priming. In summary, our data suggest that pDCs employ a unique mechanism of pDCexo-mediated antigen transfer to cDCs for cross-priming.

CD8 + T cell immune responses are critical for combating infectious diseases and tumours 1 , 2 – 3 . Antigen cross-presentation, primarily occurring at the endoplasmic reticulum (ER) of dendritic cells, is essential for protein-based vaccines to induce CD8 + T cell responses 4 . Current efforts have focused on antigen delivery at the tissue and cellular levels, whereas subcellular delivery has been limited to facilitating antigen escape from lysosomes into the cytosol. In the absence of a small-sized high-affinity ER-targeting molecule, the importance of the ‘last mile’ from the cytosol to the ER remains elusive. Here we developed stimulator of interferon genes (STING) agonist-based ER-targeting molecules (SABER), which effectively deliver antigens to the ER and cluster key machinery in cross-presentation to form microreactors by folding the ER membrane. Conjugation of SABER to various antigens substantially enhances the induction of CD8 + T cell immune responses to tumour neoantigens and conserved viral epitopes, far exceeding that achieved by mixtures of antigens with STING agonists or conventional adjuvants. SABER also retains a potent adjuvant effect, effectively enhancing the ability of a SARS-CoV-2 subunit vaccine to induce broadly neutralizing antibodies. This study provides a high-affinity ER-targeting delivery system and vaccine adjuvant, demonstrating that precise subcellular delivery targeting the last mile of cross-presentation can lead to a qualitative leap. STING agonist-based endoplasmic reticulum-targeting molecules can be conjugated directly onto antigens to deliver them to the cross-presentation pathway, improving CD8 + T cell responses against tumours and viruses.

Acquisition of cell-associated tumor antigens by type 1 dendritic cells (cDC1) is essential to induce and sustain tumor specific CD8 + T cells via cross-presentation. Here we show that capture and engulfment of cell associated antigens by tissue resident lung cDC1 is inhibited during progression of mouse lung tumors. Mechanistically, loss of phagocytosis is linked to tumor-mediated downregulation of the phosphatidylserine receptor TIM4, that is highly expressed in normal lung resident cDC1. TIM4 receptor blockade and conditional cDC1 deletion impair activation of tumor specific CD8 + T cells and promote tumor progression. In human lung adenocarcinomas, TIM4 transcripts increase the prognostic value of a cDC1 signature and predict responses to PD-1 treatment. Thus, TIM4 on lung resident cDC1 contributes to immune surveillance and its expression is suppressed in advanced tumors. Acquisition of dying tumor cell-associated antigens is an essential step for the initiation of anti-tumor immune response by conventional type 1 dendritic cells (cDC1). Here the authors show that the loss of TIM4 expression in lung tumor associated cDC1 is associated with less efficient uptake of cell associated antigens and reduction of CD8 + T cell activation in advanced lung tumors.

Over the last decades, vaccine development has advanced significantly in pursuing higher safety with less side effects. However, this is often accompanied by a reduction in vaccine immunogenicity and an increased dependency on adjuvants to enhance vaccine potency. Especially for diseases like cancer, it is important that therapeutic vaccines contain adjuvants that promote strong T cell responses. An important mode of action for such adjuvants is to prolong antigen exposure to dendritic cells (DCs) and to induce their maturation. These mature DCs are extremely effective in the activation of antigen-specific T cells, which is a pre-requisite for induction of potent and long-lasting cellular immunity. For the activation of CD8 cytotoxic T cell responses, however, the exogenous vaccine antigens need to gain access to the endogenous MHCI presentation pathway of DCs, a process referred to as antigen cross-presentation. In this review, we will focus on recent insights in clinically relevant vaccine adjuvants that impact DC cross-presentation efficiency, including aluminum-based nanoparticles, saponin-based adjuvants, and Toll-like receptor ligands. Furthermore, we will discuss the importance of adjuvant combinations and highlight new developments in cancer vaccines. Understanding the mode of action of adjuvants in general and on antigen cross-presentation in DCs in particular will be important for the design of novel adjuvants as part of vaccines able to induce strong cellular immunity.

Therapeutic cancer vaccination is an attractive strategy because it induces T cells of the immune system to recognize and kill tumour cells in cancer patients. However, it remains difficult to generate large numbers of T cells that can recognize the antigens on cancer cells using conventional vaccine carrier systems 1 , 2 . Here we show that α -Al 2 O 3 nanoparticles can act as an antigen carrier to reduce the amount of antigen required to activate T cells in vitro and in vivo . We found that α -Al 2 O 3 nanoparticles delivered antigens to autophagosomes in dendritic cells, which then presented the antigens to T cells through autophagy. Immunization of mice with α -Al 2 O 3 nanoparticles that are conjugated to either a model tumour antigen or autophagosomes derived from tumour cells resulted in tumour regression. These results suggest that α -Al 2 O 3 nanoparticles may be a promising adjuvant in the development of therapeutic cancer vaccines. Alumina nanoparticles can help induce the immune system to destroy tumours, making them a promising candidate for a therapeutic cancer vaccine.

Dendritic cells (DCs) that orchestrate mucosal immunity have been studied in mice. Lahl and colleagues characterize human gut DC populations and define their relationship to previously described human and mouse DCs. Dendritic cells (DCs) that orchestrate mucosal immunity have been studied in mice. Here we characterized human gut DC populations and defined their relationship to previously studied human and mouse DCs. CD103 + Sirpα − DCs were related to human blood CD141 + DCs and to mouse intestinal CD103 + CD11b − DCs and expressed markers of cross-presenting DCs. CD103 + Sirpα + DCs aligned with human blood CD1c + DCs and mouse intestinal CD103 + CD11b + DCs and supported the induction of regulatory T cells. Both CD103 + DC subsets induced the T H 17 subset of helper T cells, while CD103 − Sirpα + DCs induced the T H 1 subset of helper T cells. Comparative analysis of transcriptomes revealed conserved transcriptional programs among CD103 + DC subsets and identified a selective role for the transcriptional repressors Bcl-6 and Blimp-1 in the specification of CD103 + CD11b − DCs and intestinal CD103 + CD11b + DCs, respectively. Our results highlight evolutionarily conserved and divergent programming of intestinal DCs.

Key Points Dendritic cells (DCs) can take up dying cells and cross-present antigens derived from the dying cells to antigen-specific CD8 + T cells. Efficient T cell cross-priming is dependent on a set of immunological signals provided by dying cells. Dying cells expose and release 'find-me' and 'eat-me' signals to attract and stimulate phagocytosis. They also release immune-stimulatory molecules known as damage-associated molecular patterns (DAMPs), which can be sensed by phagocytes. Cell death pathways are interconnected with innate immune pathways, resulting in simultaneous execution of cell death and activation of inflammatory pathways within dying cells. Molecules that are generated de novo as a consequence of the programmed cell death and inflammatory pathways within dying cells are named inducible DAMPs (iDAMPs), in contrast to constitutive DAMPs (cDAMPs), which are present before the initiation of cell death. Hence, iDAMPs released by dying cells reflect the various stress pathways that are engaged during cell death. iDAMPs may be the products of active RNA transcription and protein translation (for example, nuclear factor-κB-dependent inflammatory cytokines), or post-translational protein modifications (such as pro-interleukin-1β cleavage by caspase 1), or protein aggregates that propagate signalling upon phagocytosis (such as apoptosis-associated speck-like protein containing a CARD (ASC) specks). In the cascade of immunological signals that leads to T cell priming, the activation of innate immune pathways within dying cells is an early immune signal that actively regulates the adaptive immune response. This Review provides an overview of the cross-presentation of antigens derived from dead cells and describes how immunological signals from dying cells influence T cell cross-priming. The authors propose a novel classification of the immunogenic signals that arise from dying cells and discuss how different forms of cell death may influence the outcome of cross-presentation. Dying cells have an important role in the initiation of CD8 + T cell-mediated immunity. The cross-presentation of antigens derived from dying cells enables dendritic cells to present exogenous tissue-restricted or tumour-restricted proteins on MHC class I molecules. Importantly, this pathway has been implicated in multiple autoimmune diseases and accounts for the priming of tumour antigen-specific T cells. Recent data have revealed that in addition to antigen, dying cells provide inflammatory and immunogenic signals that determine the efficiency of CD8 + T cell cross-priming. The complexity of these signals has been evidenced by the multiple molecular pathways that result in cell death and that have now been shown to differentially influence antigen transfer and immunity. In this Review, we provide a detailed summary of both the passive and active signals that are generated by dying cells during their initiation of CD8 + T cell-mediated immunity. We propose that molecules generated alongside cell death pathways — inducible damage-associated molecular patterns (iDAMPs) — are upstream immunological cues that actively regulate adaptive immunity.

Dying cells initiate adaptive immunity by providing both antigens and inflammatory stimuli for dendritic cells, which in turn activate CD8+ T cells through a process called antigen cross-priming. To define how different forms of programmed cell death influence immunity, we established models of necroptosis and apoptosis, in which dying cells are generated by receptor-interacting protein kinase-3 and caspase-8 dimerization, respectively. We found that the release of inflammatory mediators, such as damage-associated molecular patterns, by dying cells was not sufficient for CD8+ T cell cross-priming. Instead, robust cross-priming required receptor-interacting protein kinase-1 (RIPK1) signaling and nuclear factor κB (NF-κB)–induced transcription within dying cells. Decoupling NF-κB signaling from necroptosis or inflammatory apoptosis reduced priming efficiency and tumor immunity. Our results reveal that coordinated inflammatory and cell death signaling pathways within dying cells orchestrate adaptive immunity.

The class III PI3K Vacuolar protein sorting 34 (Vps34) plays a role in both canonical and noncanonical autophagy, key processes that control the presentation of antigens by dendritic cells (DCs) to naive T lymphocytes. We generated DC-specific Vps34-deficient mice to assess the contribution of Vps34 to DC functions. We found that DCs from these animals have a partially activated phenotype, spontaneously produce cytokines, and exhibit enhanced activity of the classic MHC class I and class II antigen-presentation pathways. Surprisingly, these animals displayed a defect in the homeostatic maintenance of splenic CD8α⁺ DCs and in the capacity of these cells to cross-present cell corpse-associated antigens to MHC class I-restricted T cells, a property that was associated with defective expression of the T-cell Ig mucin (TIM)-4 receptor. Importantly, mice deficient in the Vps34-associated protein Rubicon, which is critical for a noncanonical form of autophagy called “Light-chain 3 (LC3)-associated phagocytosis” (LAP), lacked such defects. Finally, consistent with their defect in the cross-presentation of apoptotic cells, DC-specific Vps34-deficient animals developed increased metastases in response to challenge with B16 melanoma cells. Collectively, our studies have revealed a critical role of Vps34 in the regulationof CD8α⁺ DC homeostasis and in the capacity of these cells to process and present antigens associated with apoptotic cells to MHC class I-restricted T cells. Our findings also have important implications for the development of small-molecule inhibitors of Vps34 for therapeutic purposes.