Explore the vast range of titles available.

Exosomes are a distinct population of extracellular vesicles of endocytic origin with a protein repertoire similar to the parent cell. Although tumour-derived exosomes harbour immunosuppressive characteristics, they also carry tumour antigens and thus potentially contribute to immune activation. The aim of this study was to examine the impact of prostate cancer exosomes on tumour antigen cross-presentation. DU145 cells, transduced with shRNA to knockdown Rab27a (DU145 KD ) that inhibits exosome secretion, triggered significantly stronger tumour-antigen-specific T cell responses when loaded onto dendritic cells (DC) than control DU145 cells. Enhanced T cell response was prevented by adding purified exogenous DU145 exosomes to DU145 KD cells, demonstrating that the dominant effect of tumour exosomes is immunosuppression and not antigen delivery. CD8 + T cell responses were impaired via exosomal regulation of DC function; exosomes triggered the expression of CD73, an ecto-5-nucleotidase responsible for AMP to adenosine hydrolysis, on DC. CD73 induction on DC that constitutively express CD39 resulted in an ATP-dependent inhibition of TNFα- and IL-12-production. We identified exosomal prostaglandin E 2 (PGE 2 ) as a potential driver of CD73 induction, as inhibition of PGE 2 receptors significantly reduced exosome-dependent CD73 induction. The results reveal a hitherto unknown suppression of DC function via exosomal PGE 2 , adding a new element to tumour exosome-immune cell cross-talk. Abbreviations: AMP: adenosine monophosphate; ATP: adenosine triphosphate; BLCL: B lymphoblastoid cell line; CME: exosomes enriched from cell line conditioned media; DC: dendritic cell; DMSO: dimethyl-sulfoxide; DU145 C : DU145 cells with irrelevant knockdown control; DU145 KD : DU145 cells with Rab27a knockdown; ELISA: enzyme-linked immunosorbent assay; FBS: fetal bovine serum; GM-CSF: granulocyte-monocyte colony stimulating factor; HLA: human lymphocyte antigen; IL: interleukin; LPS: lipopolysaccharide; mfi: mean fluorescence intensity; PBMC: peripheral blood mononuclear cells; PBS: phosphate buffer solution; PGE 2 : prostaglandin E 2 ; TRF: time-resolved fluorescence.

An efficient and cost‐effective therapeutic vaccine is highly desirable for the prevention and treatment of cancer, which helps to strengthen the immune system and activate the T cell immune response. However, initiating such an adaptive immune response efficiently remains challenging, especially the deficient antigen presentation by dendritic cells (DCs) in the immunosuppressive tumor microenvironment. Herein, an efficient and dynamic antigen delivery system based on the magnetically actuated OVA‐CaCO3‐SPIO robots (OCS‐robots) is rationally designed for active immunotherapy. Taking advantage of the unique dynamic features, the developed OCS‐robots achieve controllable motion capability under the rotating magnetic field. Specifically, with the active motion, the acid‐responsiveness of OCS‐robots is beneficial for the tumor acidity attenuating and lysosome escape as well as the subsequent antigen cross‐presentation of DCs. Furthermore, the dynamic OCS‐robots boost the crosstalk between the DCs and antigens, which displays prominent tumor immunotherapy effect on melanoma through cytotoxic T lymphocytes (CTLs). Such a strategy of dynamic vaccine delivery system enables the active activation of immune system based on the magnetically actuated OCS‐robots, which presents a plausible paradigm for incredibly efficient cancer immunotherapy by designing multifunctional and novel robot platforms in the future. Magnetically actuated biodegradable CaCO3‐based nanorobots are able to improve the crosstalk between antigens and DCs, followed by efficient lysosome escape and antigen cross‐presentation of DCs. This work presents a facial and multifunctional smart robot platform for efficient cancer therapy with immunomodulation‐enhanced antitumor immunity, which represents an outstanding therapeutic strategy for tumor immunotherapy.

Tumor mutational burden (TMB), usually representing high immunogenicity, cannot always predict treatment response of immune checkpoint blockade (ICB). Here, it is showed that defective antigen cross‐presentation in type 1 conventional dendritic cells (cDC1) is responsible for lacking tumor‐specific cytotoxic T lymphocytes (CTLs) in triple‐negative breast cancer (TNBC) patients. Mechanistically, tumor cytosolic CDC37, shuttled via extracellular vesicles (EVs) into the endosomes of intratumor dendritic cells (DCs), inhibits antigen cross‐presentation by locking antigen binding to HSP90 and precluding their translocation from endosomes to cytoplasm. CDC37 knockdown in tumor cells or inhibiting CDC37/HSP90 interaction in DCs efficiently promotes antigen translocation and enhances their cross‐presentation, which improves ICB therapeutic responses. Clinically, high tumor CDC37 expression is associated with low infiltration of antigen‐specific CTLs and poor ICB efficacy in TNBC patients. Therefore, tumor EV‐shuttled CDC37 locks antigen/chaperone interaction and impairs antigen cross‐presentation in DCs. Moreover, targeting CDC37 is promising to enhance anti‐tumor immunity and reverse ICB resistance. Extracellular vesicle (EV)‐packaged CDC37 are released from TMBhiCTLlo breast cancer cells with high CDC37 expression, and internalized into endo/phagosomes of dendritic cells (DCs). Within these compartments, CDC37 locked HSP90–antigen complex, preventing antigen release into the cytosol. Consequently, antigens are not processed by cytosolic proteasomes and fail to be presented on MHC class I molecules at the DC surface.

Despite the tremendous amount of basic knowledge in cancer immunity gained and many transitional approaches attempted, current cancer immunotherapies are still far from reaching universal effectiveness. Therefore, next‐generation cancer immunotherapies would emerge from deepened mechanistic insights on the full spectrum of cellular and molecular interactions between cancer cells and their immune sentinels. This review embarks on an exhaustive exploration of the cardinal immunological principles that catalyze robust cancer surveillance and their potential escapes and recapitulate the state‐of‐art understanding of both receptors and corresponding immune cell types involved. Both tumor intrinsic and tumor microenvironmental mediators of immune escapes are outlined in the context of current clinic applications. Following emphasizing the exceptional requisites that effective cancer immunity cycle must meet, specific cellular subsets crucial for igniting tumor immunity, notably effector and helper T cells alongside antigen presentation cells are examined, focusing on their close interactions in both antigen‐dependent and ‐independent manners. Such intricate interactions form dynamic immune hubs at the tumor site, holding promising key functionality in rendering effective cancer retreat. Grounded on these recent insights, refined immunotherapeutic strategies, especially those bolstering priming based anticancer effector functions are advocated. Our review focused on how specific cellular subsets crucial for igniting tumor immunity cycle, notably effector and helper T cells alongside antigen presentation cells, interact closely in both antigen‐dependent and ‐independent manners (within centered ring) adjacent to cancer cells. Such intricate interactions form an integrated and dynamic immune hub at the tumor site, where a delicate balance between immune killing of cancer cells versus cancer immune suppression and escape is reached. To tilt the balance favoring cancer eradication, mechanistic insights inspired us to advocate for three specific refined strategies (on the peripheral of the ring) to bolster antitumor vaccine designs by ① delivering the antigen to draining lymph node, and to maintain engaged DC status within TME and DC's vital mobility back to the tumor draining lymph node (purple arrows), ② targeting the antigen to be engulfed by specialized cDC1 antigen presentation cells, and ③ promoting antigen cross‐presentation by engaging relevant cellular signaling pathways as well as purposefully shuttling endolytic protein cargoes through particular routs among diverse cellular compartments.

Cross‐presentation by MHCI is optimally efficient in type 1 dendritic cells (DC) due to their high capacity for antigen processing. However, through specific pathways, other DCs, such as type 2 DCs and inflammatory DCs (iDCs) can also cross‐present antigens. FcγR‐mediated uptake by type 2 DC and iDC subsets mediates antibody‐dependent cross‐presentation and activation of CD8+ T cell responses. Here, an important role for the p84 regulatory subunit of PI3Kγ in mediating efficient cross‐presentation of exogenous antigens in otherwise inefficient cross‐presenting cells, such as type 2 DCs and GM‐CSF‐derived iDCs is identified. FcγR‐mediated cross‐presentation is shown in type 2 and iDCs depend on the enzymatic activity of the p84/p110γ complex of PI3Kγ, which controls the activity of the NADPH oxidase NOX2 and ROS production in murine spleen type 2 DCs and GM‐CSF‐derived iDCs. In contrast, p84/p110γ is largely dispensable for cross‐presentation by type 1 DCs. These findings suggest that PI3Kγ‐targeted therapies, currently considered for oncological practice, may interfere with the ability of type 2 DCs and iDCs to cross‐present antigens contained in immune complexes. Type 2 DCs and inflammatory DCs can cross‐present antibody‐bound antigens. Type 1 DCs, considered the dominant cross‐presenting population, are not involved in this process. In type 2 DCs, antibody‐antigen complexes recognized by FcγR induce the selective activation of the p84/p110 complex of PI3Kγ. This activation promotes antigen cross‐presentation by inducing NOX2‐mediated ROS production in the endocytic pathway.

Due to the high-quality immunogenicity of tumor-derived autophagosomes (DRibbles), we aimed to explore the antitumor ability and mechanism of DRibble-loaded dendritic cells (DRibble-DCs). DRibbles extracted from the oral squamous cell carcinoma cell line SCC7 express specific LC3-II and ubiquitination marker. Immunization of mice with the DRibble-DCs vaccine led to the proliferation and differentiation of CD3 CD4 IFN-γ and CD3 CD8 IFN-γ T cells. The expression of proteins in endoplasmic reticulum stress (ERS) pathways was determined by Western blotting. Additionally, the functional properties of the DRibble-DCs were examined in mice, and regulatory T cells were measured by flow cytometry. Excellent biocompatibility was observed in vitro when DCs were loaded with DRibbles. T cells of lymph nodes and spleens from mice immunized with DRibble-DCs had cytotoxic effects on SCC7 cells. DCs homeostasis and ERS-related proteins were affected by DRibbles. Moreover, the DRibble-DCs vaccine achieved significantly better antitumor efficacy than DRibbles and tumor cell lysate-loaded DCs. The results validated the antitumor immune responses to the DRibble-DCs vaccine in vivo and in vitro. The ERS pathway can be affected by DRibbles.

The contribution of dendritic cell (DC) antigen cross-presentation to the activation of CD8 T lymphocytes for immune defense against tumors, viruses, and intracellular pathogens has been recognized widely. Although originally thought to be an exclusive characteristic of DCs, recently also other immune cells, particularly macrophages, have been shown capable of cross-presentation. Here we provide an overview of and evidence on cross-presentation by macrophages. As we discuss, it is now firmly established that various types of tissue-resident macrophages are able to cross-present via similar cellular pathways as DCs. This is based on a wide range of antigens in macrophages from many different tissue origins such as blood, tumors, and lymphoid tissue. However, the physiological relevance of macrophage cross-presentation with potential contributions to activation of CD8 T lymphocytes is still mostly unknown. While cross-presentation by various types of proinflammatory macrophages might be involved in cross-priming of naive CD8 T lymphocytes, it might also be involved in local reactivation of memory and/or effector CD8 T lymphocytes. Moreover, cross-presentation by anti-inflammatory macrophages could be related to immune tolerance. Because cross-presentation promotes the initiation and potentiation of antigen-specific CD8 T lymphocyte responses, stimulating macrophages to cross-present antigen might be a promising strategy for antitumor or antiviral therapies.

The lungs are constantly exposed to environmental and infectious agents such as dust, viruses, fungi, and bacteria that invade the lungs upon breathing. The lungs are equipped with an immune defense mechanism that involves a wide variety of immunological cells to eliminate these agents. Various types of dendritic cells (DCs) and macrophages (MACs) function as professional antigen-presenting cells (APCs) that engulf pathogens through endocytosis or phagocytosis and degrade proteins derived from them into peptide fragments. During this process, DCs and MACs present the peptides on their major histocompatibility complex class I (MHC-I) or MHC-II protein complex to naïve CD8 + or CD4 + T cells, respectively. In addition to these cells, recent evidence supports that antigen-specific effector and memory T cells are activated by other lung cells such as endothelial cells, epithelial cells, and monocytes through antigen presentation. In this review, we summarize the molecular mechanisms of antigen presentation by APCs in the lungs and their contribution to immune response.

The human Vγ9Vδ2 T cell is a unique cell type that holds great potential in immunotherapy of cancer. In particular, the therapeutic potential of this cell type in adoptive cell therapy (ACT) has gained interest. In this regard optimization of in vitro expansion methods and functional characterization is desirable. We show that Vγ9Vδ2 T cells, expanded in vitro with zoledronic acid (Zometa or ZOL) and Interleukin-2 (IL-2), are efficient cancer cell killers with a trend towards increased killing efficacy after prolonged expansion time. Thus, Vγ9Vδ2 T cells expanded for 25 days in vitro killed prostate cancer cells more efficiently than Vγ9Vδ2 T cells expanded for 9 days. These data are supported by phenotype characteristics, showing increased expression of CD56 and NKG2D over time, reaching above 90% positive cells after 25 days of expansion. At the early stage of expansion, we demonstrate that Vγ9Vδ2 T cells are capable of cross-presenting tumor antigens. In this regard, our data show that Vγ9Vδ2 T cells can take up tumor-associated antigens (TAA) gp100, MART-1 and MAGE-A3 - either as long peptide or recombinant protein – and then present TAA-derived peptides on the cell surface in the context of HLA class I molecules, demonstrated by their recognition as targets by peptide-specific CD8 T cells. Importantly, we show that cross-presentation is impaired by the proteasome inhibitor lactacystin. In conclusion, our data indicate that Vγ9Vδ2 T cells are broadly tumor-specific killers with the additional ability to cross-present MHC class I-restricted peptides, thereby inducing or supporting tumor-specific αβTCR CD8 T cell responses. The dual functionality is dynamic during in vitro expansion, yet, both functions are of interest to explore in ACT for cancer therapy.

Oligodendrocyte progenitor cells (OPCs) account for about 5% of total brain and spinal cord cells, giving rise to myelinating oligodendrocytes that provide electrical insulation to neurons of the CNS. OPCs have also recently been shown to regulate inflammatory responses and glial scar formation, suggesting functions that extend beyond myelination. Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifaceted phagocytic receptor that is highly expressed in several CNS cell types, including OPCs. Here, we have generated an oligodendroglia-specific knockout of LRP1, which presents with normal myelin development, but is associated with better outcomes in two animal models of demyelination (EAE and cuprizone). At a mechanistic level, LRP1 did not directly affect OPC differentiation into mature oligodendrocytes. Instead, animals lacking LRP1 in OPCs in the demyelinating CNS were characterized by a robust dampening of inflammation. In particular, LRP1-deficient OPCs presented with impaired antigen cross-presentation machinery, suggesting a failure to propagate the inflammatory response and thus promoting faster myelin repair and neuroprotection. Our study places OPCs as major regulators of neuroinflammation in an LRP1-dependent fashion.