scholarly journals Modelling the Immune Response to Cancer: An Individual-Based Approach Accounting for the Difference in Movement Between Inactive and Activated T Cells

2018 ◽  
Vol 80 (6) ◽  
pp. 1539-1562 ◽  
Author(s):  
Fiona R. Macfarlane ◽  
Tommaso Lorenzi ◽  
Mark A. J. Chaplain
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Activated T Cells ◽  
Immune Response To Cancer ◽  
The Difference

scholarly journals Immunological effect of irreversible electroporation on solid tumors

2020 ◽  
Author(s):  
Xiaoxia Guo ◽  
Fang Du ◽  
Qin Liu ◽  
Yan Guo ◽  
Qingbing Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Nk Cells ◽  
Irreversible Electroporation ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Activated T Cells ◽  
Immunological Effect ◽  
Immunological Effects ◽  
And Control

Abstract Background This study intends to investigate the immunological effects of tumor ablation with irreversible electroporation (IRE). Methods We evaluated the systemic immune response in patients with hepatocellular carcinoma (HCC) after IRE treatment. Furthermore, we analyzed the tumor infiltrating T lymphocytes and the level of serum cytokines in IRE and control groups of tumor-bearing mice. Results We observed that IRE induced an increase in WBC, neutrophil and monocyte counts and a decrease in lymphocyte count 1 day post-IRE and returned to baseline values within 7 days in the patients. Meanwhile, circulating CD4+ T cell subsets, but not CD8+, decreased 1 day post-IRE. The activated T cells and natural killer (NK) cells increased, and regulatory T (Treg) cells decreased. Furthermore, a significant increase in cytotoxic CD8+ T cells infiltration was observed on ablative tumors in mice. The level of serum IFN-γ also significantly increased in the IRE group. Conclusions Our study demonstrated that IRE not only induced immediate innate immune response dominated by the increase of neutrophils, monocytes and NK cells, but also upregulated activated T cells and downregulated Treg. Meanwhile, the results from the animal model indicated that IRE could induce antitumor adaptive immunity dominated by cytotoxic CD8+ T cells.

scholarly journals PD-L1 Checkpoint Blockade Augments Anti-Tumor Immune Response of GD2 or HER2-Bsab Ex Vivo Armed T-Cells (EVAT) Therapy in Osteosarcoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1959-1959
Author(s):  
Jeong A Park ◽  
Hong fen Guo ◽  
Hong Xu ◽  
Nai-Kong V. Cheung
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Bispecific Antibody ◽  
Ex Vivo ◽  
Activated T Cells ◽  
The Impact ◽  
Anti Tumor Activity

Background Ex Vivo Armed T-cells (EVAT) carrying zeptomoles (10-21M) of T-cell engaging GD2-bispecific antibody (GD2-EVAT) or HER2-bispecific antibodies (HER2-EVAT) have potent anti-tumor activity against GD2(+) and/or HER2(+) solid tumors. Strategies to further optimize this approach are highly relevant. PD-1 is a key immune checkpoint receptor expressed mainly by activated T-cells and mediates immune suppression by binding to its ligands PD-L1 or PD-L2. Upregulation of PD-L1 has been found in many cancers including osteosarcoma and associated with aggressive disease and poor outcome. While the use of immune checkpoint inhibitors (ICIs) seems logical, the ideal timing when combined with T-cell engaging bispecific antibody (T-BsAb) or EVAT has yet to be defined. Here, we described the effects of anti-PD-1 or anti-PD-L1 antibodies on GD2-EVAT or HER2-EVAT therapy and explored the impact of its timing in the treatment of osteosarcoma which is GD2(+), HER2(+) and PD-L1(+). Methods GD2-BsAb and HER-BsAb were built using the IgG(L)-scFv format (Can Immunol Res, 3:266, 2015, Oncoimmunology, PMID:28405494). T-cells from healthy volunteer donors were isolated, and cultured ex vivo in the presence of CD3/CD28 beads plus 30 IU/mL of interleukin 2 (IL-2). Between day 7 and day 14, activated T-cells (ATCs) were harvested and armed for 20 minutes at room temperature with GD2-BsAb or HER2-BsAb. In vivo anti-tumor activity against GD2(+), HER2(+), and PD-L1(+) osteosarcoma cell line xenografts was tested in BALB-Rag2-/-IL-2R-γc-KO mice. Anti-human PD-1 antibody (pembrolizumab, anti-PD-1) or anti-human PD-L1 antibody (atezolizumab, anti-PD-L1) were tested for synergy with GD2-EVAT or HER2-EVAT therapy. Results The PD-1 expression increased among T-cells that circulated in the blood, that infiltrated the spleen or the tumor after EVAT therapy. While anti-PD-L1 combination therapy with GD2-EVAT or HER2-EVAT improved anti-tumor response against osteosarcoma (P=0.0123 and P=0.0004), anti-PD-1 did not (all P>0.05). The addition of anti-PD-L1 significantly increased T-cell survival in blood and T-cell infiltration of tumor when compared to GD2-EVAT or HER2-EVAT alone (all P<0.0001). Treatment of GD2-EVAT or anti-PD-L1 plus GD2-EVAT downregulated GD2 expression on tumors, but anti-PD-1 plus GD2-EVAT did not. For the next step we tested the impact of different combination schedules of ICIs on GD2-EVAT therapy. Concurrent anti-PD-1 (6 doses along with GD2-EVAT therapy) interfered with GD2-EVAT, while sequential anti-PD-1 (6 doses after GD2-EVAT) did not make a significant effect (P>0.05). On the other hand, while the concurrent use of anti-PD-L1 did not show benefit on GD2-EVAT, sequentially administered anti-PD-L1 produced a significant improvement in tumor control when compared to anti-PD-L1 or GD2-EVAT alone (P=0.002 and P=0.018). When anti-PD-L1 treatment was extended (12 doses after GD2-EVAT), the anti-tumor effect was most pronounced compared to GD2-EVAT alone (P <0.0001), which translated into improved survival (P=0.0057). These in vivo anti-tumor responses were associated with increased CD8(+) tumor infiltrating lymphocytes (TILs) of tumor. Conclusion In the arming platform, large numbers of target-specific T-cells can be generated, and this EVAT therapy is a highly effective cellular treatment with high potency in preclinical models. In addition, the advantage of ex vivo cytokine release following T-cell arming and activation could reduce or avoid life threatening cytokine storm if such activation was to proceed in vivo. Adoptive T-cell therapy induced immune response upregulates the inhibitory immune checkpoint PD-1/PD-L1 pathway, and combination treatment with anti-PD-L1 antibody, especially when combined as sequential therapy and continuously treated, significantly improved anti-tumor effect of EVAT, partly through increase in CD8(+) TILs infiltration. Disclosures Xu: MSK: Other: co-inventors in patents on GD2 bispecific antibody and HER2 bispecific antibody. Cheung:Ymabs: Patents & Royalties, Research Funding.

scholarly journals Distinct cellular immune profiles in the airways and blood of critically ill patients with COVID-19

2020 ◽  
Author(s):  
Anno Saris ◽  
Tom D.Y. Reijnders ◽  
Esther J. Nossent ◽  
Alex R. Schuurman ◽  
Jan Verhoeff ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Effector Memory ◽  
Activated T Cells ◽  
Immune Profile ◽  
Prolonged Icu Stay

AbstractOur understanding of the coronavirus disease-19 (COVID-19) immune response is almost exclusively derived from studies that examined blood. To gain insight in the pulmonary immune response we analysed BALF samples and paired blood samples from 17 severe COVID-19 patients. Macrophages and T cells were the most abundant cells in BALF. In the lungs, both CD4 and CD8 T cells were predominantly effector memory cells and expressed higher levels of the exhaustion marker PD-1 than in peripheral blood. Prolonged ICU stay associated with a reduced proportion of activated T cells in peripheral blood and even more so in BALF. T cell activation in blood, but not in BALF, was higher in fatal COVID-19 cases. Increased levels of inflammatory mediators were more pronounced in BALF than in plasma. In conclusion, the bronchoalveolar immune response in COVID-19 has a unique local profile that strongly differs from the immune profile in peripheral blood.SummaryThe bronchoalveolar immune response in severe COVID-19 strongly differs from the peripheral blood immune profile. Fatal COVID-19 associated with T cell activation blood, but not in BALF.

scholarly journals Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells

2008 ◽  
Vol 9 (12) ◽  
pp. 1356-1363 ◽  
Author(s):  
Baoli Yang ◽  
Denise L Gay ◽  
Megan K L MacLeod ◽  
Xiao Cao ◽  
Tamara Hala ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Adaptive Immune Response ◽  
Activated T Cells ◽  
Adaptive Immune

CD4+T cells suppress immune response to cancer: novel targets for antitumor efforts

2012 ◽  
Vol 8 (5) ◽  
pp. 401-403 ◽  
Author(s):  
Allison Nelson ◽  
Sajitha Nair ◽  
Srinivas Nagaraj
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd4 T Cells ◽  
Immune Response To Cancer ◽  
Novel Targets

scholarly journals Low-Dose Acetylsalicylic Acid Reduces T Cell Immune Activation: Potential Implications for HIV Prevention

2021 ◽  
Vol 12 ◽  
Author(s):  
Julie Lajoie ◽  
Monika M. Kowatsch ◽  
Lucy W. Mwangi ◽  
Geneviève Boily-Larouche ◽  
Julius Oyugi ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Acetylsalicylic Acid ◽  
Immune Activation ◽  
Genital Tract ◽  
Low Dose ◽  
Female Genital Tract ◽  
Activated T Cells ◽  
Clinical Trial Registration

IntroductionAcetylsalicylic acid (ASA) is a well-known and safe anti-inflammatory. At low-dose, it is prescribed to prevent secondary cardiovascular events in those with pre-existing conditions and to prevent preeclampsia. Little is known about how low-dose ASA affects the immune response. In this study, we followed women to assess how ASA use modifies T cells immune phenotypes in the blood and at the genital tract.MethodsHIV uninfected women from Kenya were enrolled in this study and followed for one month to assess baseline responses including systemic/mucosal baseline immune activation. Participants then received 81mg of ASA daily for 6 weeks to assess changes to T cell immune activation (systemic and mucosal) relative to baseline levels.ResultsThe concentration of ASA measured in the blood was 58% higher than the level measured at the female genital tract. In the blood, the level of ASA was inversely correlated with the following: the proportion of Th17 expressing HLA-DR (p=0.04), the proportion of effector CD4+ T cells expressing CCR5 (p=0.03) and the proportion of CD8+Tc17 expressing CCR5 (p=0.04). At the genital tract, ASA use correlated with a decreased of activated CD4+T cells [CD4+CCR5+CD161+ (p=0.02) and CD4+CCR5+CD95+ (p=0.001)].ConclusionThis study shows that ASA use impacts the immune response in both the systemic and genital tract compartments. This could have major implications for the prevention of infectious diseases such as HIV, in which the virus targets activated T cells to establish an infection. This could inform guidelines on ASA use in women.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT02079077.

scholarly journals Synergistic Effects of Acoustics-based Therapy and Immunotherapy in Cancer Treatment

2021 ◽  
Author(s):  
Yuheng Bao ◽  
Jifan Chen ◽  
Pintong Huang ◽  
Weijun Tong
Keyword(s):  
Immune Response ◽  
Cancer Treatment ◽  
Cancer Immunotherapy ◽  
Synergistic Effects ◽  
Research Field ◽  
Cancer Tissue ◽  
Activated T Cells ◽  
Immunological Recognition ◽  
The Status ◽  
Immune Response To Cancer

Cancer is an intractable disease and has ability to escape immunological recognition. Cancer immunotherapy to enhance the autogenous immune response to cancer tissue is reported to be the most promising method for cancer treatment. After the release of damage-associated molecular patterns, dendritic cells come mature and then recruit activated T cells to induce immune response. To trigger the release of cancer associated antigens, cancer acoustics-based therapy has various prominent advantages and has been reported in various research. In this review, we classified the acoustics-based therapy into sonopyrolysis-, sonoporation-, and sonoluminescence-based therapy. Then, detailed mechanisms of these therapies are discussed to show the status of cancer immunotherapy induced by acoustics-based therapy in quo. Finally, we express some future prospects in this research field and make some predictions of its development direction

scholarly journals P01.09 Dual signalling protein 107 triggers innate and adaptive immune response towards tumour cells

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A12-A13
Author(s):  
E Cendrowicz ◽  
LJ Jacob ◽  
S Greenwald ◽  
G Huls ◽  
M Dranitzki-Elhalel ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Fluorescent Protein ◽  
Model System ◽  
Tumour Cells ◽  
Carcinoma Cells ◽  
Therapeutic Antibodies ◽  
T And B Cells ◽  
Activated T Cells ◽  
Part Time

BackgroundDual signalling protein 107 (DSP107) is a trimeric fusion protein consisting of the extracellular domains of human SIRPα and 4-1BBL. SIRPα binds to CD47, frequently overexpressed on cancer cells, and 41BBL binds to 41BB on activated T-cells. The SIRPα domain triggers the innate immune response by inhibiting the CD47/SIRPα ‘don’t eat me’ signalling. It thus promotes phagocytosis of cancer cells by granulocytes, macrophages and dendritic cells. With its other side, 41BBL domain binds to pre-activated T cells and stimulates their expansion, cytokine production and cytolytic effector function. Our hypothesis is that augmented phagocytosis and improved co-localization of immune cells will lead to better antigen presentation towards activated T and B cells and the generation of memory T and B cells will be enforced. As result DSP107 might lead to immunity after rechallenge with the same tumour type.Materials and MethodsPrimary phagocytes were incubated with stained tumour cells in presence or absence of DSP107 or/and therapeutic antibodies. Fluorescence microscopy measured uptake of tumour cells by macrophages. FACS identified primary granulocytes positive for CD11b staining and membrane dye. HT1080-41BB cells were mixed with HT1080-CD47 or HT1080-wt in presence of DSP107 and IL-8 release to supernatant was measured by ELISA. Further, primary T cells were co-cultured with αCD3Fc and fluorescent protein transduced carcinoma cells at different DSP107 concentrations.ResultsThe number of granulocytes that phagocyte tumour cells was increased in presence of DSP107. Further, DSP107 not only stimulated more macrophages to engulf tumour cells, but also the number of tumour cells that were taken up per phagocyte rose. Already enhanced phagocytosis of tumour cells by therapeutic antibodies (e.g. Cetuximab, Rituximab and Trastuzumab) was improved even further by DSP107. A model system showed that activation of the 41BB/41BBL axis by DSP107 was dependent on cross-linking via CD47 domain. This indicates low off-target T cell activation. Apart from the model system, DSP107 stimulated primary T cells in co-culture with carcinoma cells (transduced to express αCD3 and a fluorescent protein). Cytolytic activity against carcinoma cells was improved and outgrowth of tumour cells was reduced in a dose dependant manner.ConclusionsDSP107 blocks the CD47/SIRPα checkpoint resulting in enhanced tumour cell phagocytosis and stimulates the 41BB/41BBL axis leading to T cell mediated tumour cell killing. DSP107 is a novel bifunctional therapeutic that targets and activates both innate and adaptive anticancer immune responses. DSP107 is a first-in-class drug candidate that can be used as a monotherapy or in combination with tumor-targeting monoclonal antibodies to trigger induction of anti-cancer immunity. DSP107 is currently tested in IND-enabling studies and clinical development is planned to commence in 2020.Disclosure InformationE. Cendrowicz: None. L.J. Jacob: A. Employment (full or part-time); Significant; KAHR Medical. S. Greenwald: A. Employment (full or part-time); Significant; KAHR Medical. G. Huls: None. M. Dranitzki-Elhalel: None. Y. Pereg: A. Employment (full or part-time); Significant; KAHR Medical. A. Chajut: A. Employment (full or part-time); Significant; KAHR Medical. E. Bremer: None.

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