scholarly journals Analysis of the Intratumoral Adaptive Immune Response in Well Differentiated and Dedifferentiated Retroperitoneal Liposarcoma

Sarcoma ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
William W. Tseng ◽  
Shruti Malu ◽  
Minying Zhang ◽  
Jieqing Chen ◽  
Geok Choo Sim ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Cd4 T Cells ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Adaptive Immune ◽  
Retroperitoneal Liposarcoma ◽  
Well Differentiated

Treatment options are limited in well differentiated (WD) and dedifferentiated (DD) retroperitoneal liposarcoma. We sought to study the intratumoral adaptive immune response and explore the potential feasibility of immunotherapy in this disease. Tumor-infiltrating lymphocytes (TILs) were isolated from fresh surgical specimens and analyzed by flow cytometry for surface marker expression. Previously reported immune cell aggregates known as tertiary lymphoid structures (TLS) were further characterized by immunohistochemistry. In all fresh tumors, TILs were found. The majority of TILs were CD4 T cells; however cytotoxic CD8 T cells were also seen (average: 20% of CD3 T cells). Among CD8 T cells, 65% expressed the immune checkpoint molecule PD-1. Intratumoral TLS may be sites of antigen presentation as DC-LAMP positive, mature dendritic cells were found juxtaposed next to CD4 T cells. Clinicopathologic correlation, however, demonstrated that presence of TLS was associated with worse recurrence-free survival in WD disease and worse overall survival in DD disease. Our data suggest that an adaptive immune response is present in WD/DD retroperitoneal liposarcoma but may be hindered by TLS, among other possible microenvironmental factors; further investigation is needed. Immunotherapy, including immune checkpoint blockade, should be evaluated as a treatment option in this disease.

Double positive CD4+CD8+ T cells are part of the adaptive immune response against Candida albicans

2019 ◽  
Vol 80 (12) ◽  
pp. 999-1005 ◽  
Author(s):  
Barbara Misme-Aucouturier ◽  
Adel Touahri ◽  
Marjorie Albassier ◽  
Francine Jotereau ◽  
Patrice Le Pape ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Candida Albicans ◽  
Cd8 T Cells ◽  
Adaptive Immune Response ◽  
Double Positive ◽  
Adaptive Immune

scholarly journals Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs

2007 ◽  
Vol 205 (1) ◽  
pp. 105-115 ◽  
Author(s):  
Andrea J. Wolf ◽  
Ludovic Desvignes ◽  
Beth Linas ◽  
Niaz Banaiee ◽  
Toshiki Tamura ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Lymph Node ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Adaptive Immune Response ◽  
Adaptive Immune ◽  
Initial Activation ◽  
Local Lymph Node

The onset of the adaptive immune response to Mycobacterium tuberculosis is delayed compared with that of other infections or immunization, and allows the bacterial population in the lungs to expand markedly during the preimmune phase of infection. We used adoptive transfer of M. tuberculosis Ag85B-specific CD4+ T cells to determine that the delayed adaptive response is caused by a delay in initial activation of CD4+ T cells, which occurs earliest in the local lung-draining mediastinal lymph node. We also found that initial activation of Ag85B-specific T cells depends on production of antigen by bacteria in the lymph node, despite the presence of 100-fold more bacteria in the lungs. Although dendritic cells have been found to transport M. tuberculosis from the lungs to the local lymph node, airway administration of LPS did not accelerate transport of bacteria to the lymph node and did not accelerate activation of Ag85B-specific T cells. These results indicate that delayed initial activation of CD4+ T cells in tuberculosis is caused by the presence of the bacteria in a compartment that cannot be mobilized from the lungs to the lymph node, where initial T cell activation occurs.

Immunomodulatory Effects and Adaptive Immune Response to Daratumumab in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3037-3037 ◽  
Author(s):  
Jakub Krejcik ◽  
Tineke Casneuf ◽  
Inger Nijhof ◽  
Bie Verbist ◽  
Jaime Bald ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Advisory Committees ◽  
Adaptive Immune ◽  
T Cell Clonality ◽  
Cell Clonality

Abstract Introduction: Daratumumab (DARA) is a novel human monoclonal antibody that targets CD38, a protein that is highly expressed on multiple myeloma (MM) cells. DARA acts through multiple immune effector-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis. In two clinical studies (NCT00574288 [GEN501] and NCT01985126 [Sirius]) of DARA monotherapy in patients with relapsed and refractory MM, overall response rates were 36% and 29%, respectively. CD38 is highly expressed in myeloma cells but also expressed in lymphocytes and other immune cell populations. Therefore, the effects of DARA on immune cell populations and adaptive immune response pathways were investigated. Methods: The patient population investigated included treated subjects with MM that were relapsed after or were refractory to ≥2 prior therapies (GEN501) or had received ≥3 prior therapies, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or were refractory to both a PI and an IMiD (Sirius). Patients assessed in this analysis were treated with 16 mg/kg DARA. When both studies were combined, median age (range) was 64 (31-84) years and median time from diagnosis was 5.12 (0.77-23.77) years. Seventy-six percent of patients had received >3 prior therapies and 91% were refractory to their last treatment. Clinical response was evaluated using IMWG consensus recommendations. Peripheral blood (PB) samples and bone marrow (BM) biopsies/aspirates were taken at prespecified time points and immunophenotyped by flow cytometry to enumerate various T-cell sub-types. T-cell clonality was measured by TCR sequencing. Antiviral T-cell response and regulatory T-cell (Treg) activity were analysed by functional in vitro assays. T-cell subpopulation counts were modelled over time with linear mixed modelling. Two group comparisons were performed using non-parametric Wilcoxon rank sum tests. Results: Data from 148 patients receiving 16 mg/kg DARA in GEN501 (n = 42) and Sirius (n = 106) were analyzed for changes in immune response. In PB, robust mean increases in CD3+ (44%), CD4+ (32%) and CD8+ (62%) T-cell counts per 100 days were seen with DARA treatment. However, responding evaluable patients (n = 45) showed significantly greater increases from baseline than nonresponders (n = 93) in CD3+ (P = 0.00012), CD4+ (P = 0.00031), and CD8+ (P = 0.00018) T cells. In BM aspirates the number of CD3+, CD4+, and CD8+ T-cells increased during treatment compared to baseline (the median percent increases were 19.95%, 5.66%, and 26.99% [n = 58]). Additionally, CD8+: CD4+ T-cell ratios significantly increased compared to baseline in both PB (P = 0.00017), and BM (P = 0.00016). T cell clonality, assessed by TCR sequencing, increased after DARA treatment compared with pretreatment (P = 0.049), with greater sums of absolute expansion in the repertoire (P = 0.037), as well as greater maximum expansion of a single clone (P = 0.048) in responders compared to nonresponders. Increased antiviral T-cell responses were observed post-DARA treatment, particularly in responders. Interestingly, a novel subpopulation of regulatory T cells was identified that expressed high levels of CD38. These cells comprised ~10% of all Tregs and were depleted by one DARA infusion. In ex vivo analyses, CD38+ Tregs appeared to be highly immune suppressive compared to CD38-Tregs. Conclusions: Robust T cell increases, increased CD8+: CD4+ ratios, increased antiviral responses, and increased T cell clonality were all observed after DARA treatment in a heavily pretreated, relapsed, and refractory patient population not expected to have strong immune responses. Improved clinical responses were associated with changes in these parameters. In addition, a sub-population of regulatory T cells expressing high CD38 levels was determined to be extremely immune suppressive and sensitive to DARA treatment. These data suggest a previously unknown immune modulatory role of DARA that may contribute to its efficacy, and a potential role for CD38 immune targeted therapies. We postulate that there are several distinct and complementary mechanisms that contribute to DARA's efficacy including increased antigen presentation through phagocytosis, targeting of immune suppressive Tregs, and increased adaptive immune responses. JK and TC contributed equally to this work. Disclosures Casneuf: Janssen: Employment. Verbist:Janssen: Employment. Bald:Janssen: Employment. Plesner:Genmab: Membership on an entity's Board of Directors or advisory committees; Roche and Novartis: Research Funding; Janssen and Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Janssen: Employment. van de Donk:Janssen Pharmaceuticals: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Weiss:Janssen and Onclave: Research Funding; Janssen and Millennium: Consultancy. Ahmadi:Janssen: Employment. Lokhorst:Genmab: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Mutis:Janssen: Research Funding; Genmab: Research Funding.

scholarly journals Single-Cell RNA Sequencing of Peripheral Blood Reveals Immune Cell Signatures in Alzheimer’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Hui Xu ◽  
Jianping Jia
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Single Cell ◽  
Immune Cells ◽  
Peripheral Blood ◽  
Immune Cell ◽  
Adaptive Immune Response ◽  
Immune Repertoire ◽  
Adaptive Immune ◽  
Peripheral Immune Cells

The peripheral immune system is thought to affect the pathology of the central nervous system in Alzheimer’s disease (AD). However, current knowledge is inadequate for understanding the characteristics of peripheral immune cells in AD. This study aimed to explore the molecular basis of peripheral immune cells and the features of adaptive immune repertoire at a single cell level. We profiled 36,849 peripheral blood mononuclear cells from AD patients with amyloid-positive status and normal controls with amyloid-negative status by 5’ single-cell transcriptome and immune repertoire sequencing using the cell ranger standard analysis procedure. We revealed five immune cell subsets: CD4+ T cells, CD8+ T cells, B cells, natural killer cells, and monocytes–macrophages cells, and disentangled the characteristic alterations of cell subset proportion and gene expression patterns in AD. Thirty-one cell type-specific key genes, comprising abundant human leukocyte antigen genes, and multiple immune-related pathways were identified by protein–protein interaction network and pathway enrichment analysis. We also found high-frequency amplification clonotypes in T and B cells and decreased diversity in T cells in AD. As clone amplification suggested the activation of an adaptive immune response against specific antigens, we speculated that the peripheral adaptive immune response, especially mediated by T cells, may have a role in the pathogenesis of AD. This finding may also contribute to further research regarding disease mechanism and the development of immune-related biomarkers or therapy.

scholarly journals Multifaceted influence of pre-mitotic cytotoxicity of primed CD8 T cells on immunity and infection

2018 ◽  
Author(s):  
Durga Bhavani Dandamudi ◽  
David A Blair ◽  
Raquel Duque do Nascimento Arifa ◽  
Juan J Lafaille ◽  
Michael L Dustin ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd8 T Cells ◽  
Secondary Infection ◽  
Granzyme B ◽  
Adaptive Immune Response ◽  
Lymphocytic Choriomeningitis ◽  
Cell Repertoire ◽  
Adaptive Immune ◽  
Window Of Vulnerability

AbstractGranzyme B mRNA is expressed in primed CD8 T cells within 12 hours, but the consequences of this for the immune response are unknown. We observed that substantial portion of the naïve CD8 T cell repertoire expressed granzyme B and became pre-mitotic cytotoxic cells (PMCs) immediately in response toListeria monocytogenesorLymphocytic choriomeningitis virusinfections. The surprising breadth arose from sufficiency of low potency peptide-MHC to induce granzyme B expression in the context of infection. PMCs killed antigen bearing dendritic cells (DCs) in a granzyme B-dependent but largely perforinindependent fashion between 1-2 days post infection. This terminated antigen presentation at 3 days and resulted in reduced clonal expansion. As additional consequences, we highlight that PMCs reduced the burden of DC-borne infectious agents, but also opened a window of vulnerability for secondary infection. Thus, PMCs serve antigen-specific, regulatory and host defence functions, that are innate-like in scale, at the onset of the adaptive immune response.

scholarly journals The Adjuvants Polyphosphazene (PCEP) and a Combination of Curdlan Plus Leptin Promote a Th17-Type Immune Response to an Intramuscular Vaccine in Mice

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 507
Author(s):  
Alyssa Chaffey ◽  
Glenn Hamonic ◽  
Dylan Chand ◽  
George K. Mutwiri ◽  
Heather L. Wilson
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd4 T Cells ◽  
Cytokine Production ◽  
Ex Vivo ◽  
Adaptive Immune Response ◽  
Vaccine Adjuvants ◽  
Adaptive Immune ◽  
Significant Production ◽  
Local Cytokine

Our aim was to determine whether polyphosphazene (PCEP), Curdlan (β-glucan, a dectin-1 agonist), and Leptin could act as adjuvants to promote a Th17-type adaptive immune response in mice. Mice were vaccinated via the intramuscular route then boosted three weeks later with Ovalbumin plus: PCEP, Leptin, Curdlan, PCEP+Curdlan, Curdlan+Leptin, or saline. Mice vaccinated with OVA+PCEP and OVA+Curdlan+Leptin showed significantly higher frequency of antigen-specific CD4+ T cells secreting IL-17 relative to OVA-vaccinated mice. No formulation increased the frequency of CD4+ T cells secreting IL-4 or IFNγ. Since activation of innate immunity precedes the development of adaptive immunity, we wished to establish whether induction of Th17-type immunity could be predicted from in vitro experiments and/or from the local cytokine environment after immunization with adjuvants alone. Elevated IL-6 and TGFβ with reduced secretion of IL-12 is a cytokine milieu known to promote differentiation of Th17-type immunity. We injected the immunostimulants or saline buffer into murine thigh muscles and measured acute local cytokine production. PCEP induced significant production of IL-6 and reduced IL-12 production in muscle but it did not lead to elevated TGFβ production. Curdlan+Leptin injected into muscle induced significant production of TGFβ and IL-17 but not IL-6 or IL-12. We also stimulated splenocytes with media or PCEP, Leptin, Curdlan, PCEP+Curdlan, Curdlan+Leptin, PCEP+Leptin, and PCEP+Curdlan+Leptin and measured cytokine production. PCEP stimulation of splenocytes failed to induce significant production of IL-6, IL-12, TGFβ, or IL-17 and therefore ex vivo splenocyte stimulation failed to predict the increased frequency of Th17-type T cells in response to the vaccine. Curdlan-stimulated splenocytes produced Th1-type, inducing cytokine, IL-12. Curdlan+/-PCEP stimulated TGF-β production and Curdlan+Leptin+/- PCEP induced secretion of IL-17. We conclude that PCEP as well as Curdlan+Leptin are Th17-type vaccine adjuvants in mice but that cytokines produced in response to these adjuvants in muscle after injection or in ex vivo cultured splenocytes did not predict their role as a Th17-type adjuvant. Together, these data suggest that the cytokine environments induced by these immunostimulants did not predict induction of an antigen-specific Th17-type adaptive immune response. This is the first report of these adjuvants inducing a Th17-type adaptive immune response.

scholarly journals Revealing the role of CD4+ T cells in viral immunity

2012 ◽  
Vol 209 (8) ◽  
pp. 1391-1395 ◽  
Author(s):  
Andrea J. Sant ◽  
Andrew McMichael
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd4 T Cells ◽  
Adaptive Immune Response ◽  
Neutralizing Antibody ◽  
Viral Immunity ◽  
Antigen Specificity ◽  
Viral Pathogens ◽  
Adaptive Immune

Protective immunity to chronic and acute viral infection relies on both the innate and adaptive immune response. Although neutralizing antibody production by B cells and cytotoxic activity of CD8+ T cells are well-accepted components of the adaptive immune response to viruses, identification of the specific role of CD4+ T cells in protection has been more challenging to establish. Delineating the contribution of CD4+ T cells has been complicated by their functional heterogeneity, breadth in antigen specificity, transient appearance in circulation, and sequestration in tissue sites of infection. In this minireview, we discuss recent progress in identifying the multiple roles of CD4+ T cells in orchestrating and mediating the immune responses against viral pathogens. We highlight several recent reports, including one published in this issue, that have employed comprehensive and sophisticated approaches to provide new evidence for CD4+ T cells as direct effectors in antiviral immunity.

Immune Cell Profiling in CML Bone Marrow By Multiplex Immunohistochemistry

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1897-1897
Author(s):  
Brück Oscar ◽  
Sami Blom ◽  
Riku Turkki ◽  
Panu E Kovanen ◽  
Antonio Ribeiro ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Cd4 T Cells ◽  
Research Funding ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Helper T Cells ◽  
Analysis Software

Abstract Background In most solid tumors, CD8+ cytotoxic T-cells and type 1 T-helper cells are associated with a positive prognosis, but a strong immunosuppressive microenvironment may hamper their effectiveness. This notion has contributed to the development of new immune-activating therapies, such as immune checkpoint inhibitors. Although having demonstrated long-term remissions in many different solid tumor types, immune checkpoint inhibitors have not been evaluated comprehensively in hematological malignancies. In this study, we aimed to characterize the cellular and molecular immunological profiles of chronic myeloid leukemia (CML) patients' bone marrow (BM) samples. Methods BM biopsies were taken at the time of diagnosis from chronic phase CML patients (n=57) treated in the Helsinki University Hospital during years 2005-2015. We used non-leukemic (NL) BM biopsies (n=10) as controls. Using hematopathologic expertise, we constructed tissue microarray (TMA) blocks from duplicate BM spots characterized with high leukemic cell infiltration. We stained TMA slides using multiplexed immunohistochemistry (IHC) combining fluorescent and chromogenic staining allowing detection of up to six markers and nuclei simultaneously. Marker panels included T and B-lymphoid (CD3, CD4, CD8, CD20), myeloid dendritic (CD11c, BDCA-1, BDCA-3), macrophage (CD68, pSTAT1, c-MAF), natural killer cell (CD3 and CD56) and leukemia cell (CD34) markers. In addition, we examined immune checkpoint molecules (PD1, CTLA4, OX40, LAG3, TIM3) and their ligands in leukemic cells (HLA-G, PD-L1, PD-L2, HLA-ABC), as well as activation markers (CD25, CD27, CD57, Granzyme B and CD45RO). We analyzed leukemia patients' immune checkpoint expression profiles quantitatively using the image analysis software Cell Profiler and cell analysis software FlowJo and compared results with NL BMs' immune cell profiles. Results The proportion of CD3+ T cells of all cells was significantly higher in CML BM vs. NL BM (median 6.0% [interquartile range (IQR) 3.6-10.7] vs. 2.1% [IQR 1.5-4.5], p=0.001). There was no significant difference in CD8+ cytotoxic T cell levels, but CD4+ helper T cells were 8-fold more abundant in CML as compared to non-leukemic BM (p<0.0001). The proportion of both memory CD45RO+CD8+ T cells (62.2% [IQR 47.4-69.8] vs. 47.3% [IQR 27.9-56.2] of CD8+ T cells, p=0.03) and memory CD45RO+CD4+ T cells (61.8% [IQR 51.8-68.5] vs. 40.0% [IQR 25.6-57.9] of CD4+ T cells, p=0.004) were significantly higher in leukemic patients. Although the proportion of PD1+CD8+ T cells did not differ between CML and NL BM, there was a significantly lower proportion of PD1+CD4+ T cells in CML BM vs. NL BM (25.1% [IQR 17.0-38.7] vs. 69.5% [IQR 50.7-77.9], p<0.0001). However, as the number of CD4+ T cells was increased in CML, the absolute number of CD4+PD1+ T cells of total cell population was 3-fold higher in CML BM than in NL BM (p=0.02). Both the proportion of OX40+CD4+ T cells (42.3% [IQR 28.7-51.6] vs. 18.1% [IQR 13.2-22.9], p=0.001) and OX40+CD8+ T cells (42.6% [IQR 25.8-60.7] vs. 12.7% [IQR 5.0-15.8], p<0.0001) were increased in leukemic patients. Interestingly, also the proportion of OX40+PD1+CD8+ T cells (25.7% [IQR 15.4-36.4] vs. 11.9% [IQR 5.0-15.8], p=0.0019) was higher in CML samples. Conclusion Multiplex IHC allows detailed characterization of immune cell subtypes and their phenotypes in BM biopsy samples. Our data show significant heterogeneity in immune cell subsets between individual patients. The CML BM is characterized with an increase in CD3+ T cells, especially helper T cells and CD45RO+ memory T cells, when compared to non-leukemic BM. Phenotypically, OX40+PD1neg T cells and OX40+PD1+ cytotoxic T cells were elevated in CML patients. The analysis of other immune cell subclasses, including inhibitory immune cells, and the correlation of histologic findings to prognostic data are ongoing. Together, they will provide a detailed understanding of BM immune cell composition in CML. Disclosures Mustjoki: Novartis: Honoraria, Research Funding; Ariad: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

scholarly journals Too Much of a Good Thing: High T Cell Count Can Kill Newborns

2019 ◽  
Vol 2 (2) ◽  
pp. 15-16
Author(s):  
Angelina Bustos ◽  
Lai Xu ◽  
Garett Dunsmore ◽  
Shokrollah Elahi
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Cd8 T Cells ◽  
Adaptive Immune Response ◽  
Spleen Cells ◽  
Robust Immune Response ◽  
Adaptive Immune ◽  
Neonatal Immunity ◽  
Low Exposure

Neonates have a weakened immune system that could be due to low exposure to pathogens resulting in low adaptive immunity and/or purposeful immune suppression to protect the weak neonate from a robust immune response. The purpose of this project is to find preliminary data to further investigate why the immune system of neonates are weaker, and to possibly improve neonatal immunity while protecting against a powerful immune response in the future.  Using processed mice spleen cells that were stained for CD4 and CD8 to be subjected to flow cytometry, an increase in the percent of helper CD4 and killer CD8 T cells were observed as the mice aged. This indicates that neonates do have a weaker immune system. Between healthy mice and mice infected with either Bordetella pertussis or Listeria, a decrease in the percent of CD4 and CD8 T cells were found, which could be because not enough time had passed for an adaptive immune response.

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