scholarly journals Spatial Distribution and Predictive Significance of Dendritic Cells and Macrophages in Esophageal Cancer Treated With Combined Chemoradiotherapy and PD-1 Blockade

2022 ◽  
Vol 12 ◽  
Author(s):  
Xiaoxue Ma ◽  
Zhoubo Guo ◽  
Xiaoying Wei ◽  
Gang Zhao ◽  
Dong Han ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Spatial Distribution ◽  
Tumor Cells ◽  
Combination Treatment ◽  
Locally Advanced ◽  
Underlying Mechanism ◽  
Stromal Compartment ◽  
Mutation Burden ◽  
Antigen Presenting ◽  
Tumor Biopsies

BackgroundThe first clinical study (NCT03671265) of first-line chemoradiotherapy combined with PD-1 blockade showed promising treatment outcomes in locally advanced esophageal squamous cell carcinoma (ESCC). However, partial patients did not respond to the combination treatment. The roles of dendritic cells (DCs) and macrophages in this combination treatment remain poorly understood.MethodsWe performed multiplexed immunofluorescence method to identify CD11c+ DCs, CD68+ macrophages, and their PD-L1- or PD-L1+ subpopulations in paired tumor biopsies (n = 36) collected at baseline and during the combination treatment (after radiation, 40 Gy) from the phase Ib trial (NCT03671265). We applied whole exome sequencing in the baseline tumor biopsies (n = 14) to estimate tumor mutation burden (TMB). We dynamically investigated the spatial distribution of DCs and macrophages under chemoradiotherapy combined with PD-1 blockade, and evaluated the association between their spatial distribution and combination outcome, and TMB.ResultsThe results showed that high percentages of PD-L1- DCs and macrophages in the baseline tumor compartment, but not in the stromal compartment, predicted improved OS and PFS. Chemoradiotherapy combined with PD-1 blockade promoted DCs and macrophages to migrate closer to tumor cells. During combination treatment, PD-L1- tumor cells were nearest to PD-L1- DCs and macrophages, while PD-L1+ tumor cells were next to PD-L1+ DCs and macrophages. High TMB was closely associated with a shorter distance from tumor cells to DCs and macrophages. Shorter distance between PD-L1+ tumor cells and PD-L1+ DCs or PD-L1- macrophages during the combination was correlated with better OS. Shorter distance between PD-L1- tumor cells and PD-L1- macrophages during combination was associated with both longer OS and PFS.ConclusionsPD-L1- or PD-L1+ DCs and macrophages exhibit distinct spatial distribution in ESCC. The close distance between tumor cells and these antigen-presenting cells (APCs) is critical to the clinical outcome in chemoradiotherapy combined with PD-1 blockade in ESCC patients. Our results highlight the predictive potential of spatial patterns of APCs in chemoradiotherapy combined with immunotherapy and reveal the underlying mechanism of APCs participating in chemoradiotherapy-induced antitumor immune response in ESCC.

scholarly journals Interleukin-12–Activated Natural Killer Cells Recognize B7 Costimulatory Molecules on Tumor Cells and Autologous Dendritic Cells

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 196-206 ◽  
Author(s):  
Anja B. Geldhof ◽  
Muriel Moser ◽  
Laurence Lespagnard ◽  
Kris Thielemans ◽  
Patrick De Baetselier
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Synergistic Effects ◽  
Antigen Presenting Cells ◽  
Interleukin 12 ◽  
Target Cells ◽  
Effector Cells ◽  
Antigen Presenting

Activation of natural killer (NK) cells in the presence of interleukin-12 (IL-12) augments the capacity of these effector cells to recognize B7-1– and B7-2–expressing target cells. These effector cells also efficiently lyse autologous B7-positive progenitor or organ-derived dendritic cells, suggesting a physiologic regulatory pathway between IL-12, NK cells, and B7-expressing antigen-presenting cells. Although IL-12–activated NK cells secreted higher levels of interferon-γ, this cytokine did not play a role in synergistic effects of IL-12 and B7 on NK activation. The B7-counterreceptor was found to be selectively upregulated on IL-2/IL-12 as compared with IL-2–activated NK cells. CD28 is functionally involved in the recognition of B7 on target cells since IL-2/IL-12–activated NK cells derived from CD28 knockout mice were strongly reduced in their capacity to lyse syngeneic B7-positive tumor cells as well as antigen-presenting cells. However, recognition of B7 on allogeneic targets did not require the expression of CD28 on the IL-2/IL-12–activated NK cells. Hence, IL-12 triggers the expression of both CD28-dependent and CD28-independent mechanisms that allow NK cells to eliminate B7-positive target cells including autologous dendritic cells.

scholarly journals Interleukin-12–Activated Natural Killer Cells Recognize B7 Costimulatory Molecules on Tumor Cells and Autologous Dendritic Cells

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 196-206 ◽  
Author(s):  
Anja B. Geldhof ◽  
Muriel Moser ◽  
Laurence Lespagnard ◽  
Kris Thielemans ◽  
Patrick De Baetselier
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Synergistic Effects ◽  
Antigen Presenting Cells ◽  
Interleukin 12 ◽  
Target Cells ◽  
Effector Cells ◽  
Antigen Presenting

Abstract Activation of natural killer (NK) cells in the presence of interleukin-12 (IL-12) augments the capacity of these effector cells to recognize B7-1– and B7-2–expressing target cells. These effector cells also efficiently lyse autologous B7-positive progenitor or organ-derived dendritic cells, suggesting a physiologic regulatory pathway between IL-12, NK cells, and B7-expressing antigen-presenting cells. Although IL-12–activated NK cells secreted higher levels of interferon-γ, this cytokine did not play a role in synergistic effects of IL-12 and B7 on NK activation. The B7-counterreceptor was found to be selectively upregulated on IL-2/IL-12 as compared with IL-2–activated NK cells. CD28 is functionally involved in the recognition of B7 on target cells since IL-2/IL-12–activated NK cells derived from CD28 knockout mice were strongly reduced in their capacity to lyse syngeneic B7-positive tumor cells as well as antigen-presenting cells. However, recognition of B7 on allogeneic targets did not require the expression of CD28 on the IL-2/IL-12–activated NK cells. Hence, IL-12 triggers the expression of both CD28-dependent and CD28-independent mechanisms that allow NK cells to eliminate B7-positive target cells including autologous dendritic cells.

scholarly journals Alterations of Dendritic Cells in Sepsis: Featured Role in Immunoparalysis

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Xia Fan ◽  
Zheng Liu ◽  
He Jin ◽  
Jun Yan ◽  
Hua-ping Liang
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Early Stage ◽  
Underlying Mechanism ◽  
Vital Role ◽  
Immune Disorder ◽  
And Function ◽  
Antigen Presenting

Sepsis, the leading cause of mortality in intensive care unit, is characterized by hyperinflammatory response in the early stage and followed by a period of immunosuppression. This immune disorder is believed to be the potent factor that is tightly associated with high mortality in sepsis. Dendritic cells (DCs) serve as professional antigen-presenting cells that play a vital role in immune response by activating T lymphocytes. During the progression of sepsis, DCs have been reported to take part in the aberrant immune response and be necessary for survival. Therefore, a better understanding of the DCs pathology will be undoubtedly beneficial for resolving the problems occurring in sepsis. This review discusses effects of sepsis on DCs number and function, including surface molecules expression, cytokines secretion, and T cell activation, and the underlying mechanism as well as some potential therapeutic strategies.

scholarly journals Microbial Antigen-Presenting Extracellular Vesicles Derived from Genetically Modified Tumor Cells Promote Antitumor Activity of Dendritic Cells

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 57
Author(s):  
Tomoko Ito ◽  
Kikuya Sugiura ◽  
Aya Hasegawa ◽  
Wakana Ouchi ◽  
Takayuki Yoshimoto ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antitumor Activity ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Ternary Complex ◽  
Binary Complex ◽  
Mouse Bone Marrow ◽  
Bacterial Antigen ◽  
Tumor Vaccines ◽  
Antigen Presenting

Tumor-derived extracellular vesicles (EVs), as tumor vaccines, carry tumor-associated antigens (TAAs), and were expected to transfer TAAs to antigen-presenting cells. However, treatment with tumor-derived EVs exhibited no obvious antitumor effect on the established tumors, likely due to their immuno-suppressive functions, and also to the poor immunogenicity of TAAs. In order to improve the immune stimulating properties, EVs expressing a highly immunogenic bacterial antigen, 6 kDa early secretory antigenic target (ESAT-6), from Mycobacterium tuberculosis were prepared by genetically modifying the parent tumor cells with a plasmid coding for ESAT-6. Cultured B16 tumor cells were transfected with a ternary complex system consisting of pDNA, polyethylenimine (PEI), and chondroitin sulfate. The cells that were transfected with the ternary complex secreted EVs with a higher number of ESAT-6 epitopes than those transfected by a conventional DNA/PEI binary complex, due to the low cytotoxicity, and durable high expression efficiency of the ternary complex systems. The EVs presenting the ESAT-6 epitope (ESAT-EV) were collected and explored as immune modulatory agents. Dendritic cells (DCs) were differentiated from mouse bone marrow cells and incubated with ESAT-EV. After incubating with the EVs for one day, the DCs expressed a significantly higher level of DC maturation marker, CD86. The DCs treated with ESAT-EV showed a significantly improved antitumor activity in tumor-bearing mice.

A combined local treatment with anti-PD-1 antibody and bone marrow derived dendritic cells after x-ray irradiation to subcutaneous melanoma in a murine model.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14541-e14541
Author(s):  
Yuzi Wang ◽  
Lue Sun ◽  
Xiaokang Li ◽  
Koji Tsuboi
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Combination Treatment ◽  
Bone Marrow Cells ◽  
Local Treatment ◽  
Activated T Cells ◽  
X Ray

e14541 Background: In situ dying and just died tumor cells after irradiation give danger signals and release tumor-specific antigens which are supposed to be incorporated into dendritic cells (DCs), and sequentially rendering T-cells activated and proliferated. However, it has been clarified that activated T-cells are killed by PD-L1 ligands on tumor cells which bind to PD-1 receptors on T-cells, consequently suppressing systemic cellular immunological response. To improve local control and prevent metastases after localized radiotherapy, we examined whether the combination of anti-PD-1 antibody and bone marrow derived DCs (BM-DCs) can enhance both the local and systemic antitumor immunoreactions after localized X-ray irradiation in a murine melanoma model. Methods: BM-DCs were induced by using GM-CSF and IL-4 from bone marrow cells taken from the femur and tibia of C57BL/6 mice. Syngeneic B16 melanoma cells implanted subcutaneously at the left thighs of C57BL/6 mice were irradiated with X-ray (8 Gy) 5 days after inoculation. After 1, 3, 5, 7 days from irradiation, induced DCs were injected directly to the tumor site, similarly, after 1, 3, 5 days from irradiation, anti-PD-1 antibody were injected intraperitoneally. To examine the systemic immunoreaction, B16 cells were also inoculated to the right side 4 days after the left side inoculation, and treated with the same protocols only on the left side. The size of tumors was monitored and survival analyses were performed. Results: The induced DCs showed the ability to incorporate antigens and to prime and proliferate T-cells in vitro. The combination treatment of anti-PD-1 antibody, BM-DCs and X-ray irradiation showed a significant delay of tumor growth compared to single or double combination treatments in vivo. In addition, this triple combination treatment significantly inhibited the tumor growth on the other side compared to other treatments. Conclusions: DCs and anti-PD-1 antibody significantly enhanced the antitumor effect of X-ray irradiation and prolonged the survival time. This combination also can induce a strong systemic antitumor immunoreaction which could treat metastatic tumors.

scholarly journals Antigen-Specific Polyclonal Cytotoxic T Lymphocytes Induced by Fusions of Dendritic Cells and Tumor Cells

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Shigeo Koido ◽  
Sadamu Homma ◽  
Eiichi Hara ◽  
Yoshihisa Namiki ◽  
Toshifumi Ohkusa ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Lymphocytes ◽  
Immune Responses ◽  
Tumor Cells ◽  
Cytotoxic T Lymphocytes ◽  
Alternative Approach ◽  
Antigen Presenting ◽  
Ctl Induction ◽  
Secondary Lymphoid Organs ◽  
Powerful Strategy

The aim of cancer vaccines is induction of tumor-specific cytotoxic T lymphocytes (CTLs) that can reduce the tumor mass. Dendritic cells (DCs) are potent antigen-presenting cells and play a central role in the initiation and regulation of primary immune responses. Thus, DCs-based vaccination represents a potentially powerful strategy for induction of antigen-specific CTLs. Fusions of DCs and whole tumor cells represent an alternative approach to deliver, process, and subsequently present a broad spectrum of antigens, including those known and unidentified, in the context of costimulatory molecules. Once DCs/tumor fusions have been infused back into patient, they migrate to secondary lymphoid organs, where the generation of antigen-specific polyclonal CTL responses occurs. We will discuss perspectives for future development of DCs/tumor fusions for CTL induction.

Hydrophobic chain modified low molecular weight polyethylenimine for efficient antigen delivery

RSC Advances ◽  
2016 ◽  
Vol 6 (17) ◽  
pp. 13636-13643 ◽  
Author(s):  
Hui Wang ◽  
Jian Chen ◽  
Jiajun Ying ◽  
Yuhong Xu ◽  
Ruilong Sheng
Keyword(s):  
Molecular Weight ◽  
Dendritic Cells ◽  
Tumor Cells ◽  
Low Molecular Weight ◽  
Antigen Delivery ◽  
Therapeutic Vaccines ◽  
Cross Presentation ◽  
Cell Responses ◽  
Hydrophobic Chain ◽  
Antigen Presenting

Developing new therapeutic vaccines to promote antigen cross-presentation in antigen-presenting cells, especially dendritic cells, is regarded as a promising approach to prime antigen-specific T cell responses against tumor cells.

scholarly journals Defective Regulation of Membrane TNFα Expression in Dendritic Cells of Glioblastoma Patients Leads to the Impairment of Cytotoxic Activity against Autologous Tumor Cells

2020 ◽  
Vol 21 (8) ◽  
pp. 2898
Author(s):  
Tamara Tyrinova ◽  
Olga Leplina ◽  
Sergey Mishinov ◽  
Marina Tikhonova ◽  
Evgeniya Dolgova ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Cytotoxic Activity ◽  
Tumor Cells ◽  
Tumor Cell Line ◽  
Autologous Tumor ◽  
Glioblastoma Cells ◽  
Tumoricidal Activity ◽  
Killer Activity ◽  
Double Stranded Dna ◽  
Antigen Presenting

Besides an antigen-presenting function and ability to induce antitumor immune responses, dendritic cells (DCs) possess a direct tumoricidal activity. We previously reported that monocyte-derived IFNα-induced DCs (IFN-DCs) of glioblastoma multiforme patients express low levels of membrane TNFα molecule (mTNFα) and have impaired TNFα/TNF-R1-mediated cytotoxicity against immortalized tumor cell line HEp-2. However, whether the observed defect could affect killer activity of glioma patient DCs against autologous tumor cells remained unclear. Here, we show that donor IFN-DCs possess cytotoxic activity against glioblastoma cell lines derived from a primary tumor culture. Granule-mediated and TNFα/TNF-R1-dependent pathways were established as the main mechanisms underlying cytotoxic activity of IFN-DCs. Glioblastoma patient IFN-DCs showed lower cytotoxicity against autologous glioblastoma cells sensitive to TNFα/TNFR1-mediated lysis, which was associated with low TNFα mRNA expression and high TACE/ADAM-17 enzyme activity. Recombinant IL-2 (rIL-2) and human double-stranded DNA (dsDNA) increased 1.5-fold cytotoxic activity of patient IFN-DCs against autologous glioblastoma cells. dsDNA, but not rIL-2, enhanced the expression of TNFα mRNA and decreased expression and activity of TACE/ADAM-17 enzyme. In addition, dsDNA and rIL-2 stimulated the expression of perforin and granzyme B (in the presence of dsDNA), suggesting the possibility of enhancing DC cytotoxicity against autologous glioblastoma cells via various mechanisms.

scholarly journals MARCH1 protects the lipid raft and tetraspanin web from MHCII proteotoxicity in dendritic cells

2018 ◽  
Vol 217 (4) ◽  
pp. 1395-1410 ◽  
Author(s):  
Jaehak Oh ◽  
Justin S.A. Perry ◽  
Heather Pua ◽  
Nicole Irgens-Möller ◽  
Satoshi Ishido ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lipid Rafts ◽  
Treg Cell ◽  
Substantial Reduction ◽  
Underlying Mechanism ◽  
Treg Cells ◽  
Membrane Domains ◽  
Significant Impairment ◽  
Quality Control Mechanism ◽  
Antigen Presenting

Dendritic cells (DCs) produce major histocompatibility complex II (MHCII) in large amounts to function as professional antigen presenting cells. Paradoxically, DCs also ubiquitinate and degrade MHCII in a constitutive manner. Mice deficient in the MHCII-ubiquitinating enzyme membrane-anchored RING-CH1, or the ubiquitin-acceptor lysine of MHCII, exhibit a substantial reduction in the number of regulatory T (Treg) cells, but the underlying mechanism was unclear. Here we report that ubiquitin-dependent MHCII turnover is critical to maintain homeostasis of lipid rafts and the tetraspanin web in DCs. Lack of MHCII ubiquitination results in the accumulation of excessive quantities of MHCII in the plasma membrane, and the resulting disruption to lipid rafts and the tetraspanin web leads to significant impairment in the ability of DCs to engage and activate thymocytes for Treg cell differentiation. Thus, ubiquitin-dependent MHCII turnover represents a novel quality-control mechanism by which DCs maintain homeostasis of membrane domains that support DC’s Treg cell–selecting function.

Neoadjuvant pembrolizumab in surgically resectable, locally advanced HPV negative head and neck squamous cell carcinoma (HNSCC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6012-6012 ◽  
Author(s):  
Ravindra Uppaluri ◽  
Paul Zolkind ◽  
Tianxiang Lin ◽  
Brian Nussenbaum ◽  
Ryan S Jackson ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Treatment Effect ◽  
Locally Advanced ◽  
Study Drug ◽  
Positive Margin ◽  
Distant Metastases ◽  
Treatment Intensification ◽  
Pathologic Features ◽  
Resected Tumor ◽  
Tumor Biopsies

6012 Background: Pembrolizumab has efficacy in metastatic HNSCC. We hypothesized that treatment intensification in surgically resectable HPV-negative, Stage III/IV HNSCC with neoadjuvant plus post-operative adjuvant (POA) pembrolizumab would be safe and reduce 1-year locoregional recurrence/distant metastases (LRR/DM) from 35% (historical: Cooper and Bernier NEJM 2004) to 15%. Methods: Phase II trial where all eligible patients received 1 dose of pembrolizumab (200 mg) prior to surgery and only those with high-risk pathologic features (HRPF: extracapsular extension/positive margin) were given POA cisplatin and radiation followed by pembrolizumab. PD-L1 staining was assessed by immunohistochemistry (9A11 antibody). Results: The study continues to enroll. Characteristics of 21 enrolled patients (pts) were median age 59 (32-87) yrs, tobacco use 81% (17 pts), clinical T2 (n = 2), T3 (n = 1), T4 (n = 18), and cN0/1 (n = 8), cN2 (n = 13). Preliminary analyses revealed five important findings: 1) No serious study drug-related AEs or unexpected surgical delays/complications, 2) No LRR/DM events in the first 10 patients with > 1-year follow-up after surgery 3) HRPF rate of 38% (95% CI: 18%-62%) (expected: 80%), 4) 43% of pts (95% CI: 22%-66%) with pathologic treatment response to neoadjuvant pembrolizumab (definition: tumor necrosis and/or giant cell/histiocytic reaction to keratinous debris in > 10% of tumor area), and 5) 48% of pts (95% CI:26%-70%) with clinical-to-pathologic downstaging. Pathologic treatment effect (TE) in ≥ 70% of the resected tumor or lymph node tissue area occurred in 6/21 pts (29%). Baseline tumor biopsies were PD-L1 positive ( > 1% of tumor cells) in 11/19 (58%) evaluable samples and in 7/8 (88%) evaluable pathologic responders. A significant correlation existed between baseline PD-L1 expression on tumor cells and pathologic treatment effect in the tumor (correlation coefficient: 0.72 and p = 0.0005). Conclusions: Neoadjuvant and adjuvant pembrolizumab was safe and well tolerated. We observed several lines of evidence supporting an anti-tumor effect in these pts with a single dose of pre-operative pembrolizumab. Further evaluation of this strategy is warranted. Clinical trial information: NCT02296684.

Sign in / Sign up

Export Citation Format

Share Document