Autophagy-assisted antigen cross-presentation

Yi, Yongxiang; Zhou, Zhansong; Su, Shu; Fang, Yuan; Twitty, Christopher G.; Hilton, Traci; Aung, Sandra; Urba, Walter J.; Fox, Bernard A.; Hu, Hong-Ming; Li, Yuhuan

doi:10.4161/onci.20059

Cited by 48 publications

(52 citation statements)

References 10 publications

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“…Autophagy has also emerged as a critical pathway for tumor antigen cross-presentation, which is determinant for the initiation of an efficient adaptive immune response (47, 48). Autophagy actively participates in antigen sequestration and delivery to DCs for cross-priming of CD8+ T cells.…”

Section: Effect Of Autophagy On Antitumor Immune Responsesmentioning

confidence: 99%

Hijacker of the Antitumor Immune Response: Autophagy Is Showing Its Worst Facet

et al. 2016

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Macroautophagy (hereafter referred to as autophagy) is a housekeeping process constitutively executed at basal level in all cells to promote cellular homeostasis by regulating organelle and protein turnover. However, autophagy deregulation caused by several stress factors, such as hypoxia, is prevalent in many cancers. It is now well established that autophagy can act as tumor suppressor or tumor promoter depending on tumor type, stage, and genetic context. In developed tumors, autophagy promotes the survival of cancer cells and therefore operates as a cell resistance mechanism. Emerging evidence point to the prominent role of autophagy in disabling the antitumor immune response by multiple overlapping mechanisms leading to tumor escape from immune cell attack mediated by both natural killer cells and cytotoxic T-lymphocytes. Such a role has inspired significant interest in applying anti-autophagy therapies as an entirely new approach to overcome tumor escape from immune surveillance, which constitutes so far a major challenge in developing more effective cancer immunotherapies. In this review, we will summarize recent reports describing how tumor cells, by activating autophagy, manage to hijack the immune system. In particular, we will focus on the emerging role of hypoxia-induced autophagy in shaping the antitumor immune response and in allowing tumor cells to outmaneuver an effective immune response and escape immunosurveillance. In keeping with this, we strongly believe that autophagy represents an attractive future therapeutic target to develop innovative and effective cancer immunotherapeutic approaches.

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Section: Effect Of Autophagy On Antitumor Immune Responsesmentioning

confidence: 99%

Hijacker of the Antitumor Immune Response: Autophagy Is Showing Its Worst Facet

et al. 2016

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“…We postulate that tumor-cell derived DRibble preparations, due to their content of SLiPs and DRiPs 22 , 23 as well as danger signals, 27 could be used as a practical immune monitoring tool for multiple types of cancers to assess the magnitude of therapy-induced T cell responses and may be useful as a vaccine for patients with prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

“…26 In this study, we analyzed transcript levels for antigens over-expressed in prostate cancers compared to the patients' normal tissue (The Cancer Genome Atlas (TCGA) PRAD Provisional database – 498 samples) for which protein was confirmed to be present in the UbiLT3 DRibble vaccine. We anticipated, also based on our in vivo mouse studies, that APCs would be required for the processing and cross-presentation of the DRibble-derived antigens, 22 , 23 , 27 allowing this approach to be used for all patients and not being restricted to HLA-A2 + patients, as is often the case for peptide-based monitoring approaches. This is, to our knowledge, the first report in which human tumor cell-line derived autophagosomes are used to monitor responses against non-viral antigens in human patient samples.…”

Section: Introductionmentioning

confidence: 99%

Autophagosome-based strategy to monitor apparent tumor-specific CD8 T cells in patients with prostate cancer

Ven

Hilton

Hu³

et al. 2018

OncoImmunology

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The immune system plays an essential role in eradicating cancer in concert with various treatment modalities. In the absence of autologous tumor material, no standardized method exists to assess T cell responses against the many antigens that may serve as cancer rejection antigens. Thus, development of methods to screen for therapy-induced anti-tumor responses is a high priority that could help tailor therapy. Here we tested whether a tumor-derived antigen source called DRibbles®, which contain a pool of defective ribosomal products (DRiPs), long-lived and short-lived proteins (SLiPs) and danger-associated molecular patterns (DAMPs), can be used to identify tumor-associated antigen (TAA)-specific responses in patients before or after immunotherapy treatment. Protein content, gene expression and non-synonymous – single nucleotide variants (ns-SNVs) present in UbiLT3 DRibbles were compared with prostate adenocarcinomas and the prostate GVAX vaccine cell lines (PC3/LNCaP). UbiLT3 DRibbles were found to share proteins, as well as match tumor sequences for ns-SNVs with prostate adenocarcinomas and with the cell lines PC3 and LNCaP. UbiLT3 DRibbles were used to monitor anti-tumor responses in patients vaccinated with allogeneic prostate GVAX. UbiLT3-DRibble-reactive CD8+ T-cell responses were detected in post-vaccine PBMC of 6/12 patients (range 0.85–22% of CD8+ cells) after 1 week in vitro stimulation (p = 0.007 vs. pre-vaccine). In conclusion, a cancer-derived autophagosome-enriched preparation, packaging over 100 proteins over-expressed in prostate cancer into microvesicles containing DAMPs, could be used to identify CD8+ T cells in peripheral blood from patients after prostate GVAX vaccination and may represent a general method to monitor anti-cancer T cell responses following immunotherapy.

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“…TLRs sense indeed a wide panel of conserved microbial components that are cumulatively referred to as “microbe-associated molecular patterns” (MAMPs), including specific nucleic acids and peculiar proteo-lipidic structures like lipopolysaccharide (LPS) 12 - 28 . Moreover, several TLRs have been shown to respond to so-called “damage-associated molecular patterns” (DAMPs), i.e., endogenous molecules that are released by stressed, dying or dead cells as a signal of danger 29 - 34 . This is for instance the case of TLR2 and TLR4, 35 - 40 both of which are expressed on the cell surface (similar to other TLRs that recognize proteo-lipidic components), 8 , 41 as well as of TLR9, 42 , 43 which is mainly expressed in the endosomal compartment (hence resembling other TLRs that detect nucleic acids) 8 , 41 …”

Section: Introductionmentioning

confidence: 99%

Trial Watch

et al. 2014

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Toll-like receptors (TLRs) are an evolutionarily conserved group of enzymatically inactive, single membrane-spanning proteins that recognize a wide panel of exogenous and endogenous danger signals. Besides constituting a crucial component of the innate immune response to bacterial and viral pathogens, TLRs appear to play a major role in anticancer immunosurveillance. In line with this notion, several natural and synthetic TLR ligands have been intensively investigated for their ability to boost tumor-targeting immune responses elicited by a variety of immunotherapeutic and chemotherapeutic interventions. Three of these agents are currently approved by the US Food and Drug Administration (FDA) or equivalent regulatory agencies for use in cancer patients: the so-called bacillus Calmette-Guérin, monophosphoryl lipid A, and imiquimod. However, the number of clinical trials testing the therapeutic potential of both FDA-approved and experimental TLR agonists in cancer patients is stably decreasing, suggesting that drug developers and oncologists are refocusing their interest on alternative immunostimulatory agents. Here, we summarize recent findings on the use of TLR agonists in cancer patients and discuss how the clinical evaluation of FDA-approved and experimental TLR ligands has evolved since the publication of our first Trial Watch dealing with this topic.

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Autophagy-assisted antigen cross-presentation

Cited by 48 publications

References 10 publications

Hijacker of the Antitumor Immune Response: Autophagy Is Showing Its Worst Facet

Hijacker of the Antitumor Immune Response: Autophagy Is Showing Its Worst Facet

Autophagosome-based strategy to monitor apparent tumor-specific CD8 T cells in patients with prostate cancer

Trial Watch

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