scholarly journals Dendritic Cells and Cancer: From Biology to Therapeutic Intervention

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 521 ◽  
Author(s):  
Wylie ◽  
Macri ◽  
Mintern ◽  
Waithman
Keyword(s):  
Dendritic Cells ◽  
Tumor Immunity ◽  
Critical Role ◽  
Cancer Therapies ◽  
Local Immunity ◽  
Dc Function ◽  
T Cell Infiltration ◽  
Anti Cancer ◽  
Heterogenous Population ◽  
Antigen Presenting

Inducing effective anti-tumor immunity has become a major therapeutic strategy against cancer. Dendritic cells (DC) are a heterogenous population of antigen presenting cells that infiltrate tumors. While DC play a critical role in the priming and maintenance of local immunity, their functions are often diminished, or suppressed, by factors encountered in the tumor microenvironment. Furthermore, DC populations with immunosuppressive activities are also recruited to tumors, limiting T cell infiltration and promoting tumor growth. Anti-cancer therapies can impact the function of tumor-associated DC and/or alter their phenotype. Therefore, the design of effective anti-cancer therapies for clinical translation should consider how best to boost tumor-associated DC function to drive anti-tumor immunity. In this review, we discuss the different subsets of tumor-infiltrating DC and their role in anti-tumor immunity. Moreover, we describe strategies to enhance DC function within tumors and harness these cells for effective tumor immunotherapy.

scholarly journals New Insights into Mechanisms of Long-term Protective Anti-tumor Immunity Induced by Cancer Vaccines Modified by Virus Infection

Biomedicines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 55 ◽  
Author(s):  
Volker Schirrmacher
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Tumor Immunity ◽  
Cancer Vaccines ◽  
Cell Mediated Immunity ◽  
Anti Cancer ◽  
Antigen Presenting ◽  
Molecular Patterns

The topic is how to achieve long-term protective anti-tumor immunity by anti-cancer vaccination and what are its mechanisms. Cancer vaccines should instruct the immune system regarding relevant cancer targets and contain signals for innate immunity activation. Of central importance is T-cell mediated immunity and thus a detailed understanding of cognate interactions between tumor antigen (TA)-specific T cells and TA-presenting dendritic cells. Microbes and their associated molecular patterns initiate early inflammatory defense reactions that can contribute to the activation of antigen-presenting cells (APCs) and to costimulation of T cells. The concommitant stimulation of naive TA-specific CD4+ and CD8+ T cells with TAs and costimulatory signals occurs in T-APC clusters that generate effectors, such as cytotoxic T lymphocytes and T cell mediated immunological memory. Information about how such memory can be maintained over long times is updated. The role that the bone marrow with its specialized niches plays for the survival of memory T cells is emphasized. Examples are presented that demonstrate long-term protective anti-tumor immunity can be achieved by post-operative vaccination with autologous cancer vaccines that are modified by virus infection.

scholarly journals Tolerogenic function of Blimp-1 in dendritic cells

2011 ◽  
Vol 208 (11) ◽  
pp. 2193-2199 ◽  
Author(s):  
Sun Jung Kim ◽  
Yong Rui Zou ◽  
Jordan Goldstein ◽  
Boris Reizis ◽  
Betty Diamond
Keyword(s):  
Dendritic Cells ◽  
Memory Function ◽  
Critical Role ◽  
Disease Process ◽  
Effector Memory ◽  
Tfh Cells ◽  
Dc Function ◽  
Tolerogenic Function

Blimp-1 has been identified as a key regulator of plasma cell differentiation in B cells and effector/memory function in T cells. We demonstrate that Blimp-1 in dendritic cells (DCs) is required to maintain immune tolerance in female but not male mice. Female mice lacking Blimp-1 expression in DCs (DCBlimp-1ko) or haploid for Blimp-1 expression exhibit normal DC development but an altered DC function and develop lupus-like autoantibodies. Although DCs have been implicated in the pathogenesis of lupus, a defect in DC function has not previously been shown to initiate the disease process. Blimp-1ko DCs display increased production of IL-6 and preferentially induce differentiation of follicular T helper cells (TFH cells) in vitro. In vivo, the expansion of TFH cells is associated with an enhanced germinal center (GC) response and the development of autoreactivity. These studies demonstrate a critical role for Blimp-1 in the tolerogenic function of DCs and show that a diminished expression of Blimp-1 in DCs can result in aberrant activation of the adaptive immune system with the development of a lupus-like serology in a gender-specific manner. This study is of particular interest because a polymorphism of Blimp-1 associates with SLE.

scholarly journals FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Vijayashree Mysore ◽  
Xavier Cullere ◽  
Joseph Mears ◽  
Florencia Rosetti ◽  
Koshu Okubo ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Infectious Diseases ◽  
Tumor Immunity ◽  
Validation Studies ◽  
Bacterial Toxins ◽  
Myeloid Neoplasms ◽  
Antigen Presenting

AbstractClassical dendritic cells (cDC) are professional antigen-presenting cells (APC) that regulate immunity and tolerance. Neutrophil-derived cells with properties of DCs (nAPC) are observed in human diseases and after culture of neutrophils with cytokines. Here we show that FcγR-mediated endocytosis of antibody-antigen complexes or an anti-FcγRIIIB-antigen conjugate converts neutrophils into nAPCs that, in contrast to those generated with cytokines alone, activate T cells to levels observed with cDCs and elicit CD8+ T cell-dependent anti-tumor immunity in mice. Single cell transcript analyses and validation studies implicate the transcription factor PU.1 in neutrophil to nAPC conversion. In humans, blood nAPC frequency in lupus patients correlates with disease. Moreover, anti-FcγRIIIB-antigen conjugate treatment induces nAPCs that can activate autologous T cells when using neutrophils from individuals with myeloid neoplasms that harbor neoantigens or those vaccinated against bacterial toxins. Thus, anti-FcγRIIIB-antigen conjugate-induced conversion of neutrophils to immunogenic nAPCs may represent a possible immunotherapy for cancer and infectious diseases.

scholarly journals CD11c+ MHCIIlo GM-CSF-bone marrow-derived dendritic cells act as antigen donor cells and as antigen presenting cells in neoepitope-elicited tumor immunity against a mouse fibrosarcoma

2018 ◽  
Vol 67 (9) ◽  
pp. 1449-1459 ◽  
Author(s):  
Hakimeh Ebrahimi-Nik ◽  
William L. Corwin ◽  
Tatiana Shcheglova ◽  
Alok Das Mohapatra ◽  
Ion I. Mandoiu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Tumor Immunity ◽  
Antigen Presenting Cells ◽  
Gm Csf ◽  
Donor Cells ◽  
Antigen Presenting

scholarly journals VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3512
Author(s):  
Sofiane Berrazouane ◽  
Alexie Doucet ◽  
Marc Boisvert ◽  
Frédéric Barabé ◽  
Fawzi Aoudjit
Keyword(s):  
Cell Adhesion ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Cancer Therapies ◽  
Anti Cancer ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Stromal Cell Derived Factor ◽  
Induced Apoptosis ◽  
Inhibition Studies

Cell adhesion plays a critical role in the development of chemoresistance, which is a major issue in anti-cancer therapies. In this study, we have examined the role of the VLA-4 integrin, a major adhesion molecule of the immune system, in the chemoresistance of T-ALL cells. We found that attachment of Jurkat and HSB-2 T-ALL cells to VCAM-1, a VLA-4 ligand, inhibits doxorubicin-induced apoptosis. However, their adhesion to fibronectin, which is mainly mediated via VLA-5, had no effect. Even the presence of the chemoattractant SDF1α (Stromal cell-derived factor-1α), which enhances the adhesion of T-ALL cells to fibronectin, did not modify the sensitivity of the cells attached on fibronectin towards doxorubicin-induced apoptosis. Mechanistically, we found that VLA-4 promoted T-ALL chemoresistance by inducing doxorubicin efflux. Our results showed that cell adhesion to both fibronectin and VCAM-1-induced Focal adhesion kinase (FAK) phosphorylation in T-ALL cells. However, only cell adhesion to VCAM-1 led to PYK2 phosphorylation. Inhibition studies indicated that FAK is not involved in doxorubicin efflux and chemoresistance, whereas PYK2 inhibition abrogated both VLA-4-induced doxorubicin efflux and chemoresistance. Together, these results indicate that the VLA-4/PYK2 pathway could participate in T-ALL chemoresistance and its targeting could be beneficial to limit/avoid chemoresistance and patient relapse.

scholarly journals 683 Type-I-interferon activates cross-dressed CD11b+conventional dendritic cells to enhance anti-tumor immunity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A711-A711
Author(s):  
Ellen Duong ◽  
Timothy Fessenden ◽  
Emi Lutz ◽  
Teresa Dinter ◽  
Leon Yim ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Tumor Immunity ◽  
Critical Role ◽  
T Cell Responses ◽  
T Cell Immunity ◽  
Type I ◽  
Cell Responses ◽  
Cell Immunity ◽  
Cross Dressing

BackgroundConventional dendritic cells (cDC) are critical mediators of protective anti-tumor CD8+ T-cell responses.1 Batf3-driven DC1 are the predominant cDC subset driving anti-tumor immunity due to their specialized ability to cross-present antigens for T-cell activation.2–4 However, the contribution of other tumor-infiltrating DC subsets such as CD11b+ DC2 to anti-tumor immunity remains poorly characterized. Recent studies suggest that under inflammation, DC subsets can exist in various functional states with differential impacts on their stimulatory potential.5–7 In this study, we sought to dissect the contributions of distinct DC states during a productive or dysfunctional anti-tumor immune response. A nuanced understanding of DC activation states in tumors and the signals that drive them carries therapeutic potential to modulate anti-tumor immunity and enhance immunotherapy responses.MethodsWe compared the DC infiltrate of a regressing tumor and a progressing tumor to study DC states. Flow immunophenotyping and RNA-sequencing was performed to profile the intratumoral DC compartment. Sorted DC subsets were co-cultured with T-cells ex vivo to evaluate their stimulatory capacity. Cross-dressing (in vivo/ex vivo) was assayed by staining for transfer of tumor-derived H-2b MHC complexes to MHC-mismatched or β2M-deficient DC.ResultsAnti-tumor CD8+ T-cell responses in Batf3-/- mice lacking DC1 were maintained in regressor tumors but not progressor tumors, suggesting DC1-independent anti-tumor immunity. Functional assays and RNA-sequencing of the intratumoral DC compartment of regressor tumors revealed a Zbtb46-dependent CD11b+ cDC activation state expressing an interferon-stimulated gene signature (ISG+ DC) that was critical for driving optimal anti-tumor CD8+ T-cell responses. Sorted ISG+ DC could activate CD8+ T-cells similar to DC1. Unlike cross-presenting DC1, however, ISG+ DC acquired antigens by cross-dressing with tumor-derived peptide-MHC, thereby bypassing the requirement for cross-presentation to initiate CD8+ T-cell-immunity. Interestingly, ISG+ DC were enriched in regressor tumors compared to progressor tumors, and this was attributable to constitutive tumor cell-intrinsic type-I-interferon (IFN-I) production in regressor tumors. Ablation of tumor cell-derived IFN-I in regressor tumors led to complete loss of anti-tumor T-cell responses in Batf3-/- mice. Conversely, addition of IFNβ to progressor tumors induced ISG+ DC and rescued anti-tumor T-cell responses in Batf3-/- mice.ConclusionsWe identified a novel IFN-I-induced activation state of CD11b+ cDC, called ISG+ DC, that was capable of driving anti-tumor CD8+ T cell immunity by cross-dressing with tumor-derived pMHC complexes in the absence of DC1. Engaging additional functional states of DC, such as ISG+ DC, will strengthen anti-tumor immunity and may improve immunotherapy responses.ReferencesMerad M, et al. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 2013;31:563–604Hildner K, et al. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 2008;322(5904)1097–100.Broz ML, et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 2014;26(5):638–52.Roberts EW, et al. Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in Melanoma. Cancer Cell 2016;30(2):324–336.Maier B, et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 2020;580(7802):257–262.Bosteels C, et al. Inflammatory Type 2 cDCs acquire features of cDC1s and macrophages to orchestrate immunity to respiratory virus infection. Immunity 2020;52(6):1039–1056.e9.Zilionis R, et al. Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species. Immunity 2019;50(5):1317–1334.e10.

scholarly journals Soluble HLA-G Inhibits Myeloid Dendritic Cell Function in HIV-1 Infection by Interacting with Leukocyte Immunoglobulin-Like Receptor B2

2010 ◽  
Vol 84 (20) ◽  
pp. 10784-10791 ◽  
Author(s):  
Jinghe Huang ◽  
Patrick Burke ◽  
Yue Yang ◽  
Katherine Seiss ◽  
Jill Beamon ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Cell Function ◽  
Critical Role ◽  
Antigen Presenting Cells ◽  
Hla Class I ◽  
Elite Controllers ◽  
Myeloid Dendritic Cells ◽  
Soluble Hla ◽  
Antigen Presenting ◽  
Hiv 1

ABSTRACT Dendritic cells represent a specialized class of professional antigen-presenting cells that are responsible for priming and maintaining antigen-specific effector cell responses and regulating immune activation by cytokine secretion. In HIV-1 infection, myeloid dendritic cells are highly dysfunctional, but mechanisms contributing to their functional alterations are not well defined. Here, we show that soluble molecules of the nonclassical major histocompatibility complex class Ib (MHC-Ib) antigen HLA-G are highly upregulated in the plasma during progressive HIV-1 infection, while levels of membrane-bound HLA-G surface expression on dendritic cells, monocytes, and T cells only slightly differ among HIV-1 progressors, HIV-1 elite controllers, and HIV-1-negative persons. These elevated levels of soluble HLA-G in progressive HIV-1 infection likely result from increased secretion of intracellularly stored HLA-G molecules in monocytes and dendritic cells and contribute to a functional disarray of dendritic cells by inhibiting their antigen-presenting properties, while simultaneously enhancing their secretion of proinflammatory cytokines. Interestingly, we observed that these immunoregulatory effects of soluble HLA-G were mainly mediated by interactions with the myelomonocytic HLA class I receptor leukocyte immunoglobulin-like receptor B2 (LILRB2; ILT4), while binding of soluble HLA-G to its alternative high-affinity receptor, LILRB1 (ILT2), appeared to be less relevant for its immunomodulatory functions on dendritic cells. Overall, these results demonstrate a critical role for soluble HLA-G in modulating the functional characteristics of professional antigen-presenting cells in progressive HIV-1 infection and suggest that soluble HLA-G might represent a possible target for immunotherapeutic interventions in HIV-1-infected persons.

Hsp90 Is Critical for the Regulation of Phenotype and Functionality of Human Dendritic Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2401-2401
Author(s):  
Jooeun Bae ◽  
Constantine Mitsiades ◽  
Tai Yu-Tzu ◽  
Jeff Martinson ◽  
Ramesh Babu Batchu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune System ◽  
T Lymphocytes ◽  
Clinical Data ◽  
Antigen Presenting Cells ◽  
Hsp90 Inhibitor ◽  
Antigen Uptake ◽  
Dc Function ◽  
Antigen Presenting ◽  
Inhibitor Treatment

Abstract Hsp90, a molecular chaperone, plays a critical role in protein folding and transport, and thereby it modulates cellular activity. Pre-clinical data shows over-expression of Hsp90 in multiple myeloma (MM) and efficacy of Hsp90 inhibitor in myeloma has been determined in vitro. Based on these results, phase I/II trial evaluating clinical efficacy of the Hsp90 inhibitor is underway in MM. Although Hsp90 inhibitor shows significant effects on tumor cells, there is limited information concerning its effects on the immune system. The objective of this study was to evaluate the effects of Geldanamycin on activity of antigen-presenting cells. Immature and mature monocyte derived dendritic cells (DC) from normal human donors were used as the source of antigen-presenting cells in this study. Geldanamycin treatment of DC for 24 hours had no effect on cell viability (>90%), however, it led to a significant down-regulation of surface antigens associated with activation (CD86, CD80), maturation (CD83) and antigen presentation (HLA-ABC, HLA-DPQR). This decline was associated with changes in gene expression levels of these antigens, however the protein expression analyzed by % positive cells was not down-regulated with the treatment. Exposure to Hsp90 inhibitor was associated with significant decreases in IL-12 secretion (untrt vs. trt = 135 vs. 21 pg/ml), antigen uptake (MFI untrt 798 vs. MFI trt 449, Dextran-FITC), and antigen processing. These changes were associated with decline in DC function, which were demonstrated by significant decrease in Hsp90-treated DC compared to untreated DC in presentation of Tetanus Toxoid to autologous T lymphocytes (untrt vs. trt = 73 % vs. 47 %, CFSE proliferation), allogeneic T lymphocytes stimulation (untrt vs. trt = 232795 cpm vs. 116876 cpm, 3H-thymidine incorporation), and induction of IFN-g secretion from allogenic T lymphocytes (untrt vs. trt = 500 vs. 30 pg/ml). Taken together, these results show significant decline in DC function following Hsp90 inhibitor treatment. Further studies are underway using MM patient samples pre- and post-Hsp90 inhibitor treatment to understand in vivo effects on the immune system. Our pre-clinical data suggests the need to consider proper sequence of various therapeutic modalities, including immunotherapy, to optimize and improve clinical outcome.

scholarly journals CD73+ Dendritic Cells in Cascading Th17 Responses of Experimental Autoimmune Uveitis-Induced Mice

2020 ◽  
Vol 11 ◽  
Author(s):  
MinHee K. Ko ◽  
Hui Shao ◽  
Henry J. Kaplan ◽  
Deming Sun
Keyword(s):  
Dendritic Cells ◽  
Critical Role ◽  
Γδ T Cells ◽  
Adenosine Monophosphate ◽  
Toll Like Receptor ◽  
Promoting Effect ◽  
Receptor Ligand ◽  
Antigen Presenting ◽  
Different Levels ◽  
Experimental Autoimmune

Previous studies have shown that CD73 is pivotal in the conversion of pro-inflammatory adenosine triphosphate into anti-inflammatory adenosine and that immune cells of the same type that express different levels of CD73 are functionally distinct. In this study we show that adenosine enhances the Th17 promoting effect of dendritic cells (DCs), and DCs expressing CD73 critically augment Th17 responses. Bone marrow dendritic cells (BMDCs) do not constantly express CD73; however, a significant portion of the BMDCs expressed CD73 after exposure to Toll-like receptor ligand, leading to stronger Th17 responses by converting adenosine monophosphate to adenosine. We show that the CD73+ BMDCs play a critical role in cascading Th17 responses, and CD73+ BMDCs are functionally augmented after treatment with Toll-like receptor ligand. Splenic antigen presenting cells (DCs) of CD73−/− mouse have a poor Th17-stimulating effect, even after exposure to lipopolysaccharide (LPS) or γδ T cells, indicating that induction of CD73+ DCs is critically involved in augmented Th17 responses. We conclude that CD73+ DCs critically trigger cascading Th17 responses, and the activated Th17 cells that express CD73 further augment Th17 responses, leading to cascading exacerbation. Hence, disabling the CD73 function of DCs should block this cascading response and mitigate Th17 responses.

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