scholarly journals Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhaohan Wei ◽  
Xiaoqiong Zhang ◽  
Tuying Yong ◽  
Nana Bie ◽  
Guiting Zhan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antibody Therapy ◽  
Suppressor Cells ◽  
Long Term Memory ◽  
Tumor Resistance ◽  
Anticancer Efficacy ◽  
T Cell Infiltration ◽  
Tumor Accumulation ◽  
Immunosuppressive Microenvironment

AbstractThe main challenges for programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) checkpoint blockade lie in a lack of sufficient T cell infiltration, tumor immunosuppressive microenvironment, and the inadequate tumor accumulation and penetration of anti-PD-1/PD-L1 antibody. Resetting tumor-associated macrophages (TAMs) is a promising strategy to enhance T-cell antitumor immunity and ameliorate tumor immunosuppression. Here, mannose-modified macrophage-derived microparticles (Man-MPs) loading metformin (Met@Man-MPs) are developed to efficiently target to M2-like TAMs to repolarize into M1-like phenotype. Met@Man-MPs-reset TAMs remodel the tumor immune microenvironment by increasing the recruitment of CD8+ T cells into tumor tissues and decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells. More importantly, the collagen-degrading capacity of Man-MPs contributes to the infiltration of CD8+ T cells into tumor interiors and enhances tumor accumulation and penetration of anti-PD-1 antibody. These unique features of Met@Man-MPs contribute to boost anti-PD-1 antibody therapy, improving anticancer efficacy and long-term memory immunity after combination treatment. Our results support Met@Man-MPs as a potential drug to improve tumor resistance to anti-PD-1 therapy.

scholarly journals PD-1 blockade-driven anti-tumor CD8+ T cell immunity requires XCR1+ dendritic cells

2020 ◽  
Author(s):  
Tianyang Mao ◽  
Eric Song ◽  
Akiko Iwasaki
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Human Cancer ◽  
Antibody Therapy ◽  
T Cell Immunity ◽  
Tumor Control ◽  
T Cell Infiltration ◽  
Cell Immunity ◽  
Clinical Responses

AbstractCD8+ T cells are required for effective anti-PD-1 (αPD-1) cancer immunotherapy. Type 1 conventional dendritic cells (cDC1s) bearing XCR1 critically mediate the initiation of protective anti-tumor CD8+ T cell responses in mice and humans. However, whether cDC1s contribute to evoking the effector function of CD8+ T cells during αPD-1 antibody therapy remains unclear. Here, by deleting cDC1s at the effector phase of αPD-1 therapy, we identify these cells as a crucial innate determinant for effective αPD-1 immunotherapy. αPD-1 treatment unleashed cDC1s to promote anti-tumor CD8+ T cell immunity, through the expansion of TCF1+ precursors and generation of TIM3+ terminally differentiated effectors. Furthermore, tumor cDC1 abundance was predictive of enhanced CD8+ T cell infiltration, higher survival, and improved clinical responses to αPD-1 therapy in human cancer patients. Together, this study reveals the requirement for cDC1s in PD-1 blockade therapy, through their ability to elicit CD8+ T cell effector responses that mediate tumor control, and highlight cDC1s as an attractive cellular target to be harnessed for novel immunotherapeutics.

scholarly journals Decreased inflammatory cytokine production of antigen-specific CD4+ T cells in NMDA receptor encephalitis

2021 ◽  
Author(s):  
Le-Minh Dao ◽  
Marie-Luise Machule ◽  
Petra Bacher ◽  
Julius Hoffmann ◽  
Lam-Thanh Ly ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Autoimmune Encephalitis ◽  
Active Immunization ◽  
Inflammatory Cytokine Production ◽  
T Cell Infiltration ◽  
Nmda Receptor Encephalitis ◽  
Nmdar Encephalitis ◽  
Disease Specific

AbstractAnti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is the most common autoimmune encephalitis with psychosis, amnesia, seizures and dyskinesias. The disease is mediated by pathogenic autoantibodies against the NR1 subunit that disrupt NMDAR function. Antibody infusion into mouse brains can recapitulate encephalitis symptoms, while active immunization resulted also in strong T cell infiltration into the hippocampus. However, whether T cells react against NMDAR and their specific contribution to disease development are poorly understood. Here we characterized the ex vivo frequency and phenotype of circulating CD4+ T helper (TH) cells reactive to NR1 protein using antigen-reactive T cell enrichment (ARTE) in 24 patients with NMDAR encephalitis, 13 patients with LGI1 encephalitis and 51 matched controls. Unexpectedly, patients with NMDAR encephalitis had lower frequencies of CD154-expressing NR1-reactive TH cells than healthy controls and produced significantly less inflammatory cytokines. No difference was seen in T cells reactive to the synaptic target LGI1 (Leucine-rich glioma-inactivated 1), ubiquitous Candida antigens or neoantigens, suggesting that the findings are disease-specific and not related to therapeutic immunosuppression. Also, patients with LGI1 encephalitis showed unaltered numbers of LGI1 antigen-reactive T cells. The data reveal disease-specific functional alterations of circulating NMDAR-reactive TH cells in patients with NMDAR encephalitis and challenge the idea that increased pro-inflammatory NMDAR-reactive T cells contribute to disease pathogenesis.

scholarly journals 49 In situ phenotypic analysis of T cells in the tumor microenvironment of a pre-clinical model of non-small cell lung cancer (NSCLC) by tissue sectioning and whole-mount immunofluorescence imaging

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A52-A52
Author(s):  
Elen Torres ◽  
Stefani Spranger
Keyword(s):  
T Cells ◽  
Spatial Distribution ◽  
T Cell ◽  
Spatial Location ◽  
Cell Infiltration ◽  
Cell Populations ◽  
Tumor Bearing ◽  
T Cell Infiltration ◽  
Volume Imaging ◽  
Whole Mount

BackgroundUnderstanding the interactions between tumor and immune cells is critical for improving current immunotherapies. Pre-clinical and clinical evidence has shown that failed T cell infiltration into lung cancer lesions might be associated with low responsiveness towards checkpoint blockade.1 For this reason, it is necessary to characterize not only the phenotype of T cells in tumor-bearing lungs but also their spatial location in the tumor microenvironment (TME). Multiplex immunofluorescence staining allows the simultaneous use of several cell markers to study the state and the spatial location of cell populations in the tissue of interest. Although this technique is usually applied to thin tissue sections (5 to 12 µm), the analysis of large tissue volumes may provide a better understanding of the spatial distribution of cells in relation to the TME. Here, we analyzed the number and spatial distribution of cytotoxic T cells and other immune cells in the TME of tumor-bearing lungs, using both 12 µm sections and whole-mount preparations imaged by confocal microscopy.MethodsLung tumors were induced in C57BL/6 mice by tail vein injection of a cancer cell line derived from KrasG12D/+ and Tp53-/- mice. Lung tissue with a diverse degree of T cell infiltration was collected after 21 days post tumor induction. Tissue was fixed in 4% PFA, followed by snap-frozen for sectioning. Whole-mount preparations were processed according to Weizhe Li et al. (2019) 2 for tissue clearing and multiplex volume imaging. T cells were labeled with CD8 and FOXP3 antibodies to identify cytotoxic or regulatory T cells, respectively. Tumor cells were labeled with a pan-Keratin antibody. Images were acquired using a Leica SP8 confocal microscope. FIJI3 and IMARIS were used for image processing.ResultsWe identified both cytotoxic and regulatory T cell populations in the TME using thin sections and whole-mount. However, using whole-mount after tissue clearing allowed us to better evaluate the spatial distribution of the T cell populations in relation to the tumor structure. Furthermore, tissue clearance facilitates the imaging of larger volumes using multiplex immunofluorescence.ConclusionsAnalysis of large lung tissue volumes provides a better understanding of the location of immune cell populations in relation to the TME and allows to study heterogeneous immune infiltration on a per-lesion base. This valuable information will improve the characterization of the TME and the definition of cancer-immune phenotypes in NSCLC.ReferencesTeng MW, et al., Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 2015;75(11): p. 2139–45.Li W, Germain RN, and Gerner MY. High-dimensional cell-level analysis of tissues with Ce3D multiplex volume imaging. Nat Protoc 2019;14(6): p. 1708–1733.Schindelin J, et al, Fiji: an open-source platform for biological-image analysis. Nat Methods 2012;9(7): p. 676–82.

501 VISTA regulates the differentiation and suppressive function of myeloid-derived suppressor cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A536-A536
Author(s):  
Juan Dong ◽  
Cassandra Gilmore ◽  
Hieu Ta ◽  
Keman Zhang ◽  
Sarah Stone ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
Immune Checkpoint ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Myeloid Derived Suppressor Cells ◽  
Checkpoint Protein ◽  
Suppressive Function

BackgroundV-domain immunoglobulin suppressor of T cell activation (VISTA) is a B7 family inhibitory immune checkpoint protein and is highly expressed on myeloid cells and T cells.1 VISTA acts as both an inhibitory ligand when expressed on antigen-presenting cells and a receptor when expressed on T cells. Our recent study has shown that VISTA is a myeloid cell-specific immune checkpoint and that blocking VISTA can reprogram suppressive myeloid cells and promote a T cell-stimulatory tumor microenvironment.2 In this study, we further demonstrate that VISTA blockade directly alters the differentiation and the suppressive function of myeloid-derived suppressor cells (MDSC).MethodsFlow cytometry was performed to examine VISTA expression on MDSCs in multiple murine tumor models including the B16BL6 melanoma model, MC38 colon cancer model, and the KPC pancreatic cancer models. To examine the role of VISTA in controlling the differentiation and suppressive function of MDSCs, we cultured wild type (WT) and VISTA.KO bone marrow progenitor cells with GM-CSF and IL-6 to induce BM -derived MDSCs.ResultsOur preliminary results show that VISTA is highly expressed on M-MDSCs in B16BL6, MC38 and KPC tumors. In BM-derived MDSCs, VISTA deletion significantly altered the signaling pathways and the differentiation of MDSCs. Multiple inflammatory signaling pathways were downregulated in VISTA KO MDSCs, resulting in decreased production of cytokines such as IL1 and chemokines such as CCL2/4/9, as well as significantly impaired their ability to suppress the activation of CD8+ T cells. The loss of suppressive function in VISTA KO MDSCs is correlated with significantly reduced expression of iNOS. To validate the results from BM-MDSCs, we sorted CD11b+CD11c-Ly6C+Ly6G- M-MDSCs and CD11b+CD11c-Ly6G+ G-MDSCs from B16BL6 tumor tissues and tested the ability of a VISTA-blocking mAb to reverse the suppressive effects of tumor-derived MDSCs. Our results show that blocking VISTA impaired the suppressive function of tumor-derived M-MDSC but not G-MDSCs.ConclusionsTaken together, these results demonstrate a crucial role of VISTA in regulating the differentiation and function of MDSCs, and that blocking VISTA abolishes MDSC-mediated T cell suppression, thereby boosting.Ethics ApprovalAll in vivo studies were reviewed and approved by Institutional Animal Care and Use Committee (Approval number 2019-2142).ReferencesXu W, Hire T, Malarkannan, S. et al. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 2018;15:438–446.Xu W, Dong J, Zheng Y, et al. Immune-checkpoint protein VISTA regulates antitumor immunity by controlling myeloid cell-mediated inflammation and immunosuppression. Cancer Immunol Res 2019;7:1497–510.

scholarly journals Agonistic CD40 antibody therapy induces tertiary lymphoid structures but impairs the response to immune checkpoint blockade in glioma

2021 ◽  
Author(s):  
Luuk van Hooren ◽  
Alessandra Vaccaro ◽  
Mohanraj Ramachandran ◽  
Konstantinos Vazaios ◽  
Sylwia Libard ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Antibody Therapy ◽  
Immune Checkpoint Blockade ◽  
Cytotoxic T Cell ◽  
Systemic Delivery ◽  
T Cell Infiltration ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

AbstractGliomas are brain tumors characterized by immunosuppression. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors but are yet to be evaluated for glioma. Here, systemic delivery of αCD40 led to cytotoxic T cell dysfunction and impaired the response to immune checkpoint inhibitors in preclinical glioma models. This was associated with an accumulation of suppressive CD11b+ B cells. However, αCD40 also induced tertiary lymphoid structures (TLS). In human glioma, TLS correlated with increased T cell infiltration indicating enhanced immune responses. Our work unveils the pleiotropic effects of αCD40 therapy in glioma, which is of high clinical relevance.

scholarly journals Expansion of Functional Myeloid-Derived Suppressor Cells in Controlled Human Malaria Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Carlos Lamsfus Calle ◽  
Rolf Fendel ◽  
Anurag Singh ◽  
Thomas L. Richie ◽  
Stephen L. Hoffman ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Malaria Infection ◽  
Malaria Vaccine ◽  
Suppressor Cells ◽  
T Cell Proliferation ◽  
Myeloid Derived Suppressor Cells ◽  
Controlled Human Malaria Infection

Malaria can cause life-threatening complications which are often associated with inflammatory reactions. More subtle, but also contributing to the burden of disease are chronic, often subclinical infections, which result in conditions like anemia and immunologic hyporesponsiveness. Although very frequent, such infections are difficult to study in endemic regions because of interaction with concurrent infections and immune responses. In particular, knowledge about mechanisms of malaria-induced immunosuppression is scarce. We measured circulating immune cells by cytometry in healthy, malaria-naïve, adult volunteers undergoing controlled human malaria infection (CHMI) with a focus on potentially immunosuppressive cells. Infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) were inoculated during two independent studies to assess malaria vaccine efficacy. Volunteers were followed daily until parasites were detected in the circulation by RT-qPCR. This allowed us to analyze immune responses during pre-patency and at very low parasite densities in malaria-naïve healthy adults. We observed a consistent increase in circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in volunteers who developed P. falciparum blood stage parasitemia. The increase was independent of preceding vaccination with a pre-erythrocytic malaria vaccine. PMN-MDSC were functional, they suppressed CD4+ and CD8+ T cell proliferation as shown by ex-vivo co-cultivation with stimulated T cells. PMN-MDSC reduced T cell proliferation upon stimulation by about 50%. Interestingly, high circulating PMN-MDSC numbers were associated with lymphocytopenia. The number of circulating regulatory T cells (Treg) and monocytic MDSC (M-MDSC) showed no significant parasitemia-dependent variation. These results highlight PMN-MDSC in the peripheral circulation as an early indicator of infection during malaria. They suppress CD4+ and CD8+ T cell proliferation in vitro. Their contribution to immunosuppression in vivo in subclinical and uncomplicated malaria will be the subject of further research. Pre-emptive antimalarial pre-treatment of vaccinees to reverse malaria-associated PMN-MDSC immunosuppression could improve vaccine response in exposed individuals.

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