scholarly journals ­ Apatinib combined with PD-L1 blockade synergistically enhances antitumor immune responses and promotes HEV formation in gastric cancer

2021 ◽  
Author(s):  
Yu Zhang ◽  
Fei Wang ◽  
Hao-ran Sun ◽  
Ya-kai Huang ◽  
Jian-peng Gao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
B Cells ◽  
Combination Therapy ◽  
Immune Responses ◽  
Cytotoxic T Cells ◽  
Antibody Therapy ◽  
Treg Cells ◽  
Cytotoxic T Cell ◽  
Immunocompetent Mice

Abstract Purpose Apatinib, an antiangiogenic drug, has showed beneficial effects only in a fraction of advanced gastric cancer (GC) patients. Given the recent success of immunotherapies, combination of apatinib with immune checkpoint inhibitor may provide sustained and potent antitumor responses. Methods Immunocompetent mice with subcutaneous MFC tumors grown were given combination of apatinib and anti-PD-L1 antibody therapy. GC tissues from patients undergoing curative resection in China were collected, and the density of HEVs, MSI status and tumor-infiltrated lymphocytes were analyzed by immunohistochemical staining. Results Combined apatinib and PD-L1 blockade therapy synergistically delayed tumor growth and increased survival in MFC-bearing immunocompetent mice. The combination therapy promoted antitumor immunity by increasing the ratio of CD8+ cytotoxic T cells to Foxp3+ Treg cells, the accumulation of CD20+ B cells and the Th1/Th2 cytokine ratio (IFN-γ/IL-10). The combination therapy induced the formation of HEVs through activation of LTβR signaling, thus promoting CD8+ cytotoxic T cell and CD20+ B cell infiltration in tumors. In clinical GC samples, the density of HEVs positively correlated with the intratumoral infiltration of CD8+ cytotoxic T cells and CD20+ B cells. MSI-high GC showed a higher density of HEVs, CD8+ cytotoxic T cells and CD20+ B cells than MSS/MSI-low GC. GC patients with high densities of HEVs, CD8+ cytotoxic T cells and CD20+ B cells had an improved prognosis with superior overall survival. Conclusion Combining apatinib with PD-L1 blockade treatment synergistically enhances antitumor immune responses and promotes HEV formation in GC.

scholarly journals Apatinib combined with PD-L1 blockade synergistically enhances antitumor immune responses and promotes HEV formation in gastric cancer

2020 ◽  
Author(s):  
Yu Zhang ◽  
Fei Wang ◽  
Haoran Sun ◽  
Yakai Huang ◽  
Jianpeng Gao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
B Cells ◽  
Combination Therapy ◽  
Immune Responses ◽  
Cytotoxic T Cells ◽  
Antibody Therapy ◽  
Treg Cells ◽  
Cytotoxic T Cell ◽  
Immunocompetent Mice

Abstract Background: Apatinib, an antiangiogenic drug, has showed beneficial effects only in a fraction of advanced gastric cancer (GC) patients. Given the recent success of immunotherapies, combination of apatinib with immune checkpoint inhibitor may provide sustained and potent antitumor responses.Methods: Immunocompetent mice with subcutaneous MFC tumors grown were given combination of apatinib and anti-PD-L1 antibody therapy. GC tissues from patients undergoing curative resection in China were collected, and the density of HEVs, MSI status and tumor-infiltrated lymphocytes were analyzed by immunohistochemical staining.Results: Combined apatinib and PD-L1 blockade therapy synergistically delayed tumor growth and increased survival in MFC-bearing immunocompetent mice. The combination therapy promoted antitumor immunity by increasing the ratio of CD8+ cytotoxic T cells to Foxp3+ Treg cells, the accumulation of CD20+ B cells and the Th1/Th2 cytokine ratio (IFN-γ/IL-10). The combination therapy induced the formation of HEVs through activation of LTβR signaling mediated by DCs, thus promoting CD8+ cytotoxic T cell and CD20+ B cell infiltration in tumors. In clinical GC samples, the density of HEVs positively correlated with the intratumoral infiltration of CD8+ cytotoxic T cells and CD20+ B cells. MSI-high GC showed a higher density of HEVs, CD8+ cytotoxic T cells and CD20+ B cells than MSS/MSI-low GC. GC patients with high densities of HEVs, CD8+ cytotoxic T cells and CD20+ B cells had an improved prognosis with superior overall survival.Conclusions: Combining apatinib with PD-L1 blockade treatment synergistically enhances antitumor immune responses and promotes HEV formation in GC.

scholarly journals Thymic selection of H-2-incompatible bone marrow cells in SCID mice. Differences in T help for induction of B cell IgG responses versus cytotoxic T cells.

1988 ◽  
Vol 168 (3) ◽  
pp. 1187-1192 ◽  
Author(s):  
R M Zinkernagel ◽  
E Rüedi ◽  
A Althage ◽  
H Hengartner ◽  
G Reimann
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
Vaccinia Virus ◽  
Cytotoxic T Cells ◽  
Scid Mice ◽  
Thymic Selection ◽  
Selection Of

Mice with congenital severe combined immunodeficiency disease (SCID) failed to mount either a T cell-independent IgM or T cell-dependent IgG anti-vesicular stomatitis virus (VSV) Indiana (IND) response. They did not generate cytotoxic T cells against lymphocytic choriomeningitis virus (LCMV) or vaccinia virus, but exhibited NK cell-like activities. When SCID mice were given bone marrow from syngeneic BALB/c (H-2d) nu/nu mice, all immune responses were expressed at control levels. If SCID mice were reconstituted with allogeneic H-2b C57BL/6 nu/nu bone marrow, the following primary anti-viral immune responses were measured. T-independent IgM anti-VSV-IND were normal, but T-dependent IgG anti-VSV-IND responses were absent. Cytotoxic T cell responses to LCMV and vaccinia virus were within normal ranges, were donor cell mediated, and were specific exclusively for the recipient SCID H-2d type. Since antigen presentation by spleen cells was functional in these chimaeras, the presented results indicate that (a) thymic selection of T cell restriction is strict; and (b) the type of T help necessary for B cells depends upon H-2-restricted contact between T and B cells, whereas, such contact-dependent help is not mandatory for the induction of virus-specific cytotoxic T cells.

Resistance of Quiescent Cells to T Cell Attack Determines Both the Efficacy and Specificity of Adoptive T Cell Therapy.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3161-3161
Author(s):  
I. Jedema ◽  
C.A.M. van Bergen ◽  
M.G.D. Kester ◽  
R. Willemze ◽  
J.H. Frederik Falkenburg
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
Target Cell ◽  
Cytotoxic T Cells ◽  
Precursor Cells ◽  
Adoptive T Cell Therapy ◽  
Target Cells ◽  
T Cell Therapy

Abstract Although profound anti-leukemic immune responses can be induced with donor lymphocyte infusions in patients with relapsed or persistent leukemia after allogeneic stem cell transplantation, (late) relapses of the same disease develop regularly even in patients initially entering a complete remission. This suggests that a subpopulation of leukemic (precursor) cells with ultimate self-renewal capacity is capable of resisting T cell attack. We hypothesized that quiescent leukemic precursor cells can evade anti-leukemic therapy by their capacity to survive and persist in the presence of competent cytotoxic T cells. In addition, selectivity of cytotoxic T cells (CTLs) for target cells in active cell cycle in general may also explain why powerful immune responses directed against antigens that are broadly expressed on all tissues of the recipient, like the male-specific HY-antigens, do not necessarily result in severe damage to all tissues of the recipient. Therefore, we determined the efficacy of high affinity CTL clones directed against allo-HLA or minor histocompatibility antigens to kill normal and leukemic hematopoietic cells in dormancy and in active cell cycle, comprising normal and leukemic CD34+ precursor cells, normal B cells, T cells and monocytes, and activated B cells (EBV-LCL) and activated T cells (PHA blasts). Using a CFSE-based cytotoxicity assay allowing the analysis of susceptibility to lysis of specific cell types within a heterogeneous target cell population, we found that all activated target cells were very efficiently lysed, resulting in 60–90% lysis already after 4 hours of exposure to the CTL clones (E/T ratios 1/1–5/1). In contrast, target cells in relative dormancy including the non-proliferating CD34+ CML stem cell fraction, unmanipulated CD34 progenitor cells, and resting T and B cells were protected from CTL-induced cell death (0–20% lysis). Since normal expression of adhesion and HLA class I molecules was shown on these dormant cells, we investigated whether decreased avidity of the T cell/target cell interaction was underlying the poor susceptibility. Therefore, we artificially enhanced the avidity by exogenous loading of the target cells with saturating concentrations of the relevant peptide. This was sufficient to restore the sensitivity to levels comparable to activated target cells, suggesting that decreased avidity of the interaction between high affinity CTL and resting target cells plays a role in the resistance phenomenon. However, even after restoration of the high avidity interaction, a small population of (leukemic) target cells (0,1–10% of the total cell population) was capable of residing, suggesting that additional factors like resistance of quiescent target cells to one or more of the T cell effector mechanisms are involved. To analyze the influence of the sensitivity to T cell lysis of specific target cell types on the specificity of adoptive T cell therapy, we used non-hematopoietic target cells like mesenchymal stem cells and biliary epithelium cells as target cells. Alloreactive T cells showed also diminished capacity to lyse these target cells (10–20% lysis). The addition of inflammatory cytokines like TNF and interferons slightly increased the recognition. In conclusion, under steady state conditions potent allo immune responses may have limited activity against quiescent target cells. Therefore in order to cure the disease, specific activation strategies and/or prolonged persistence of specific T cells will be needed to achieve a potent anti-leukemic effect with controlled GVHD.

scholarly journals Impact of Placenta-Derived Mesenchymal Stem Cells Treatment on Patients with Severe Lung Injury Caused by COVID-19 Pneumonia: Clinical and Immunological Aspect

2021 ◽  
Author(s):  
Mei-Chuan Chen ◽  
Kevin Shu-Leung Lai ◽  
Ko-Ling Chien ◽  
Sing-Teck Teng ◽  
Yuh-Rong Lin ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
B Cells ◽  
Lung Injury ◽  
Immune Responses ◽  
Critically Ill ◽  
Treg Cells ◽  
Control Group ◽  
Current Standard

Abstract Background:The novel coronavirus disease 2019 (COVID-19) has been a global pandemic health issue since 30, January, 2020. Mortality rate was as high as more than 50% in critically ill patients. The Stem cell treatment is effective in refractory severe critically ill COVID-19 patients, but immune regulation mechanisms have not been reported well. Therefore, we evaluate the clinical efficacy and immune modulation of placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) in severe critically ill COVID-19 infection who are refractory to current standard therapies.Methods:Intravenous infusion of 1 × 107 MatriPlax was given to five severe COVID-19 patients at Day 0 and day 4. Serum inflammatory markers and immune profiles were studied at Day 0, 4 and 8. Clinical parameters and 28-days mortality were compared between treated group and control group.Results:The treatment group had no 28-days mortality and Murray’s lung injury score was significantly improved compared with control group. After treatment, Ferritin, C-reactive protein (CRP) and Lactate dehydrogenases (LDH) were significantly reduced and lymphopenia was improved. IL-6, IL-1β, IFN-γ and IL-2 were significantly decreased together with decrease in IL-10 reflecting decreasing intensity of inflammation. Immune cell profiles showed increase in CD4+ T cells (CD4+ naïve T cells, CD4+ memory T cells subtypes), Treg cells, CD19+ B cells (and CD19+ naive B cells, CD27+ switched B cells subtypes) and dendritic cells, and a significant decrease in CD14+ monocytes (and CD16- classical, CD16+ non-classical subtypes) monocytes as well as plasma/plasmablast cells. pc-MSCs treatment suppressed hyper-inflammatory states of innate immune responses to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoted CD4+ T cells and CD19+ B cells towards adaptive immune responses.Conclusion:The intravenous transplantation of Matriplax was safe and effective for severe critically ill COVID-19 patients, especially those who were refractory to current standard care and immunosuppressive therapies

scholarly journals Human fetal liver MSCs are more effective than adult bone marrow MSCs for their immunosuppressive, immunomodulatory, and Foxp3+ T reg induction capacity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yi Yu ◽  
Alejandra Vargas Valderrama ◽  
Zhongchao Han ◽  
Georges Uzan ◽  
Sina Naserian ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Cytotoxic T Cells ◽  
Cell Contact ◽  
Adult Bone Marrow ◽  
Adult Bone

Abstract Background Mesenchymal stem cells (MSCs) exhibit active abilities to suppress or modulate deleterious immune responses by various molecular mechanisms. These cells are the subject of major translational efforts as cellular therapies for immune-related diseases and transplantations. Plenty of preclinical studies and clinical trials employing MSCs have shown promising safety and efficacy outcomes and also shed light on the modifications in the frequency and function of regulatory T cells (T regs). Nevertheless, the mechanisms underlying these observations are not well known. Direct cell contact, soluble factor production, and turning antigen-presenting cells into tolerogenic phenotypes, have been proposed to be among possible mechanisms by which MSCs produce an immunomodulatory environment for T reg expansion and activity. We and others demonstrated that adult bone marrow (BM)-MSCs suppress adaptive immune responses directly by inhibiting the proliferation of CD4+ helper and CD8+ cytotoxic T cells but also indirectly through the induction of T regs. In parallel, we demonstrated that fetal liver (FL)-MSCs demonstrates much longer-lasting immunomodulatory properties compared to BM-MSCs, by inhibiting directly the proliferation and activation of CD4+ and CD8+ T cells. Therefore, we investigated if FL-MSCs exert their strong immunosuppressive effect also indirectly through induction of T regs. Methods MSCs were obtained from FL and adult BM and characterized according to their surface antigen expression, their multilineage differentiation, and their proliferation potential. Using different in vitro combinations, we performed co-cultures of FL- or BM-MSCs and murine CD3+CD25−T cells to investigate immunosuppressive effects of MSCs on T cells and to quantify their capacity to induce functional T regs. Results We demonstrated that although both types of MSC display similar cell surface phenotypic profile and differentiation capacity, FL-MSCs have significantly higher proliferative capacity and ability to suppress both CD4+ and CD8+ murine T cell proliferation and to modulate them towards less active phenotypes than adult BM-MSCs. Moreover, their substantial suppressive effect was associated with an outstanding increase of functional CD4+CD25+Foxp3+ T regs compared to BM-MSCs. Conclusions These results highlight the immunosuppressive activity of FL-MSCs on T cells and show for the first time that one of the main immunoregulatory mechanisms of FL-MSCs passes through active and functional T reg induction.

scholarly journals Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexandra J. Spencer ◽  
Paul F. McKay ◽  
Sandra Belij-Rammerstorfer ◽  
Marta Ulaszewska ◽  
Cameron D. Bissett ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
T Cells ◽  
Immune Responses ◽  
Viral Vectors ◽  
Cytotoxic T Cells ◽  
Antibody Responses ◽  
Limited Data ◽  
Vectored Vaccine ◽  
Cellular Immune

AbstractSeveral vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.

scholarly journals Selective Induction of Th2-Attracting Chemokines CCL17 and CCL22 in Human B Cells by Latent Membrane Protein 1 of Epstein-Barr Virus

2004 ◽  
Vol 78 (4) ◽  
pp. 1665-1674 ◽  
Author(s):  
Takashi Nakayama ◽  
Kunio Hieshima ◽  
Daisuke Nagakubo ◽  
Emiko Sato ◽  
Masahiro Nakayama ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Epstein Barr Virus ◽  
Cytotoxic T Cells ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT Chemokines are likely to play important roles in the pathophysiology of diseases associated with Epstein-Barr virus (EBV). Here, we have analyzed the repertoire of chemokines expressed by EBV-infected B cells. EBV infection of B cells induced expression of TARC/CCL17 and MDC/CCL22, which are known to attract Th2 cells and regulatory T cells via CCR4, and also upregulated constitutive expression of MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5, which are known to attract Th1 cells and cytotoxic T cells via CCR5. Accordingly, EBV-immortalized B cells secreted these chemokines, especially CCL3, CCL4, and CCL22, in large quantities. EBV infection or stable expression of LMP1 also induced CCL17 and CCL22 in a B-cell line, BJAB. The inhibitors of the TRAF/NF-κB pathway (BAY11-7082) and the p38/ATF2 pathway (SB202190) selectively suppressed the expression of CCL17 and CCL22 in EBV-immortalized B cells and BJAB-LMP1. Consistently, transient-transfection assays using CCL22 promoter-reporter constructs demonstrated that two NF-κB sites and a single AP-1 site were involved in the activation of the CCL22 promoter by LMP1. Finally, serum CCL22 levels were significantly elevated in infectious mononucleosis. Collectively, LMP1 induces CCL17 and CCL22 in EBV-infected B cells via activation of NF-κB and probably ATF2. Production of CCL17 and CCL22, which attract Th2 and regulatory T cells, may help EBV-infected B cells evade immune surveillance by Th1 cells. However, the concomitant production of CCL3, CCL4, and CCL5 by EBV-infected B cells may eventually attract Th1 cells and cytotoxic T cells, leading to elimination of EBV-infected B cells at latency III and to selection of those with limited expression of latent genes.

scholarly journals Upregulated Expression of Cytotoxicity-Related Genes in IFN-γKnockout Mice withSchistosoma japonicumInfection

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Xiaotang Du ◽  
Jingjiao Wu ◽  
Meijuan Zhang ◽  
Yanan Gao ◽  
Donghui Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Schistosoma Japonicum ◽  
Fas Ligand ◽  
Acute Infection ◽  
Acquired Resistance ◽  
Parasite Burden ◽  
Cytotoxic T Cell ◽  
Igg Antibody

It is well accepted that IFN-γis important to the development of acquired resistance against murine schistosomiasis. However, thein vivorole of this immunoregulatory cytokine in helminth infection needs to be further investigated. In this study, parasite burden and host immune response were observed in IFN-γknockout mice (IFNg KO) infected withSchistosoma japonicumfor 6 weeks. The results suggested that deficiency in IFN-γled to decreased egg burden in mice, with low schistosome-specific IgG antibody response and enhanced activation of T cells during acute infection. Microarray and qRT-PCR data analyses showed significant upregulation of some cytotoxicity-related genes, including those from the granzyme family, tumor necrosis factor, Fas Ligand, and chemokines, in the spleen cells of IFNg KO mice. Furthermore, CD8+cells instead of NK cells of IFNg KO mice exhibited increased transcription of cytotoxic genes compared with WT mice. Additionally,Schistosoma japonicum-specific egg antigen immunization also could activate CD8+T cells to upregulate the expression of cytotoxic genes in IFNg KO mice. Our data suggest that IFN-γis not always a positive regulator of immune responses. In certain situations, the disruption of IFN-γsignaling may up-regulate the cytotoxic T-cell-mediated immune responses to the parasite.

scholarly journals P2.03-37 The Efficiency of Octamer-4 Specific Cytotoxic T Cells Induce By CD40-B Cells in Killing Lung Cancer Stem-Like Cells

2018 ◽  
Vol 13 (10) ◽  
pp. S730
Author(s):  
X. Zhang ◽  
J. Xu ◽  
F. Hu ◽  
H. Wang ◽  
X. Zheng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
B Cells ◽  
Cytotoxic T Cells

scholarly journals Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hee Young Na ◽  
Yujun Park ◽  
Soo Kyung Nam ◽  
Jiwon Koh ◽  
Yoonjin Kwak ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Prognostic Significance

Abstract Background Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). Methods We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. Results Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. Conclusions Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.

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