scholarly journals Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy

2019 ◽  
Author(s):  
Alok Kumar ◽  
Kenji Chamoto ◽  
Partha S. Chowdhury ◽  
Tasuku Honjo
Keyword(s):  
Cell Proliferation ◽  
Small Molecules ◽  
Mhc Class I ◽  
Tumor Model ◽  
T Cell Proliferation ◽  
Mitochondrial Activity ◽  
Cancer Treatments ◽  
Immunosuppressive Property ◽  
Develop Strategy ◽  
Bilateral Tumor

AbstractPD-1 blockade therapy has revolutionized cancer treatments. However, a substantial population of patients is unresponsive. To rescue unresponsive patients, the mechanism of unresponsiveness to PD-1 blockade therapy must be elucidated. Using a ‘bilateral tumor model’ where responsive and unresponsive tumors were inoculated into different sides of the mouse belly, we demonstrated that unresponsive tumors can be categorized into two groups: with and without systemic immunosuppressive property (SIP). The SIP-positive tumors released uncharacterized, non-proteinaceous small molecules which inhibited T cell proliferation and mitochondrial activation. By contrast, the SIP-negative B16 tumor, escaped from immunity by losing MHC class I expression. Unresponsiveness of SIP-positive tumors was partially overcome by improving the mitochondrial function with a mitochondrial activator; this was not successful to B16, which employs immune ignorance. These results demonstrated that our ‘bilateral tumor model’ was useful for stratifying tumors to investigate the mechanism of unresponsiveness and develop strategy for proper combination therapy.

scholarly journals Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Alok Kumar ◽  
Kenji Chamoto ◽  
Partha S Chowdhury ◽  
Tasuku Honjo
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Small Molecules ◽  
Mhc Class I ◽  
Tumor Model ◽  
T Cell Proliferation ◽  
Mitochondrial Activity ◽  
Cancer Treatments ◽  
Immunosuppressive Property ◽  
Bilateral Tumor

PD-1 blockade therapy has revolutionized cancer treatments. However, a substantial population of patients is unresponsive. To rescue unresponsive patients, the mechanism of unresponsiveness to PD-1 blockade therapy must be elucidated. Using a ‘bilateral tumor model’ where responsive and unresponsive tumors were inoculated into different sides of the mouse belly, we demonstrated that unresponsive tumors can be categorized into two groups: with and without systemic immunosuppressive property (SIP). The SIP-positive tumors released uncharacterized, non-proteinaceous small molecules that inhibited mitochondrial activation and T cell proliferation. By contrast, the SIP-negative B16 tumor escaped from immunity by losing MHC class I expression. Unresponsiveness of SIP-positive tumors was partially overcome by improving the mitochondrial function with a mitochondrial activator; this was not successful for B16, which employs immune ignorance. These results demonstrated that the ‘bilateral tumor model’ was useful for stratifying tumors to investigate the mechanism of unresponsiveness and develop a strategy for proper combination therapy.

GITR Agonism Enhances Cellular Metabolism to Support CD8+ T-cell Proliferation and Effector Cytokine Production in a Mouse Tumor Model

2018 ◽  
Vol 6 (10) ◽  
pp. 1199-1211 ◽  
Author(s):  
Simran S. Sabharwal ◽  
David B. Rosen ◽  
Jeff Grein ◽  
Dana Tedesco ◽  
Barbara Joyce-Shaikh ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Cytokine Production ◽  
Cellular Metabolism ◽  
Tumor Model ◽  
Cd8 T Cell ◽  
T Cell Proliferation ◽  
Mouse Tumor ◽  
Mouse Tumor Model ◽  
Effector Cytokine

scholarly journals Lipocalin 2 regulates expression of MHC class I molecules in Mycobacterium tuberculosis-infected dendritic cells via ROS production

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ji-Ae Choi ◽  
Soo-Na Cho ◽  
Junghwan Lee ◽  
Sang-Hun Son ◽  
Doan Tam Nguyen ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Proliferation ◽  
Dendritic Cells ◽  
Mycobacterium Tuberculosis ◽  
Mhc Class I ◽  
Class I ◽  
T Cell Proliferation ◽  
Oxygen Species ◽  
Lipocalin 2 ◽  
Mhc Class I Molecules

Abstract Background Iron has important roles as an essential nutrient for all life forms and as an effector of the host defense mechanism against pathogenic infection. Lipocalin 2 (LCN2), an innate immune protein, plays a crucial role in iron transport and inflammation. In the present study, we examined the role of LCN2 in immune cells during Mycobacterium tuberculosis (Mtb) infection. Results We found that infection with Mtb H37Ra induced LCN2 production in bone marrow-derived dendritic cells (BMDCs). Notably, expression of MHC class I molecules was significantly reduced in LCN2−/− BMDCs during Mtb infection. The reduced expression of MHC class I molecules was associated with the formation of a peptide loading complex through LCN2-mediated reactive oxygen species production. The reduced expression of MHC class I molecules affected CD8+ T-cell proliferation in LCN2−/− mice infected with Mtb. The difference in the population of CD8+ effector T cells might affect the survival of intracellular Mtb. We also found a reduction of the inflammation response, including serum inflammatory cytokines and lung inflammation in LCN2−/− mice, compared with wild-type mice, during Mtb infection. Conclusions These data suggest that LCN2-mediated reactive oxygen species affects expression of MHC class I molecules in BMDCs, leading to lower levels of CD8+ effector T-cell proliferation during mycobacterial infection.

scholarly journals Pluripotent Stem Cell-Derived Hepatocytes Inhibit T Cell Proliferation In Vitro through Tryptophan Starvation

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 24
Author(s):  
Marco Romano ◽  
Raul Elgueta ◽  
Daniel McCluskey ◽  
Ana Maria Ortega-Prieto ◽  
Emilie Stolarczyk ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Stem Cell ◽  
Regenerative Medicine ◽  
Mhc Class I ◽  
Pluripotent Stem Cell ◽  
T Cell Proliferation ◽  
Cell Type ◽  
Mhc Class I Molecules

Regenerative medicine aims to replace damaged tissues by stimulating endogenous tissue repair or by transplanting autologous or allogeneic cells. Due to their capacity to produce unlimited numbers of cells of a given cell type, pluripotent stem cells, whether of embryonic origin or induced via the reprogramming of somatic cells, are of considerable therapeutic interest in the regenerative medicine field. However, regardless of the cell type, host immune responses present a barrier to success. The aim of this study was to investigate in vitro the immunological properties of human pluripotent stem cell (PSC)-derived hepatocyte-like cells (HLCs). These cells expressed MHC class I molecules while they lacked MHC class II and co-stimulatory molecules, such as CD80 and CD86. Following stimulation with IFN-γ, HLCs upregulated CD40, PD-L1 and MHC class I molecules. When co-cultured with allogeneic T cells, HLCs did not induce T cell proliferation; furthermore, when T cells were stimulated via αCD3/CD28 beads, HLCs inhibited their proliferation via IDO1 and tryptophan deprivation. These results demonstrate that PSC-derived HLCs possess immunoregulatory functions, at least in vitro.

scholarly journals Clinically relevant SMAC mimetics do not enhance human T cell proliferation or cytokine production

2021 ◽  
Author(s):  
Ashley Burton ◽  
Brittany Ligman ◽  
Claire Kearney ◽  
Susan E Murray
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Small Molecules ◽  
Tumor Immunity ◽  
T Cell Proliferation ◽  
Human T Cell ◽  
Human T Cells ◽  
Anti Cancer ◽  
Smac Mimetics

Secondary mitochondria-derived activator of caspases (SMAC) mimetics are being tested in dozens of clinical trials to treat cancer. These small molecules mimic endogenous molecules that promote apoptosis by antagonizing inhibitors of apoptosis (IAPs), which are commonly overexpressed in cancer cells. In T cells, IAPs function to restrain non-canonical NF-kB signaling. Thus, it has been suggested that in addition to their direct anti-cancer mechanism of action, SMAC mimetics may activate T cells, thereby promoting anti-tumor immunity. Here, we tested the effect of three clinically relevant SMAC mimetics on the proliferation and activation of primary human T cells. As previously reported, SMAC mimetics killed tumor cells and activated non-canonical NF-kB in T cells at clinically relevant doses. Surprisingly, none of the SMAC mimetics augmented T cell proliferation or effector function. These results question the assumption that SMAC mimetics are likely to boost anti-tumor immunity in cancer patients.

scholarly journals Impact of Small Molecules Immunosuppressants on P-Glycoprotein Activity and T-cell Function

2012 ◽  
Vol 15 (3) ◽  
pp. 407 ◽  
Author(s):  
Inés Llaudó ◽  
Linda Cassis ◽  
Joan Torras ◽  
Oriol Bestard ◽  
Marcel·la Franquesa ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Small Molecules ◽  
Cd8 T Cells ◽  
Cell Function ◽  
The Other ◽  
T Cell Subsets ◽  
T Cell Proliferation ◽  
P Glycoprotein

Purpose. P-glycoprotein (Pgp) is a member of the ABC-transporter family that transports substances across cellular membranes acting as an efflux pump extruding drugs out of the cells. Pgp plays a key role on the pharmacokinetics of several drugs. Herein, we have studied the effects of immunosuppressants on Pgp function, assessing rhodamine-123 (Rho123) uptake and efflux in different T-cell subsets. Methods. Different immunosuppressants such as Cyclosporine (CsA), Rapamycin (Rapa) and Tacrolimus (Tac) were used to assess the in vitro effect on Pgp function of main T-cell subsets among healthy volunteers. We measured Rho123 uptake, efflux and kinetic of extrusion in CD4+ and CD8+ subsets by flow cytometry. Antigen-specific memory T-cell responses were assessed by measuring T-cell proliferation and cytokine secretion using an allogeneic mixed lymphocyte reaction. Results. Rho123 uptake in groups treated with CsA and CsA+Rapa was significantly decreased compared to non-treated group and the other immunosupressants in both T cells subsets. Pgp activity was also reduced in CsA and CsA+Rapa compared to the other immunosupressants but it was only significant in the CsA group for CD8+ subset. Kinetic extrusion of Rho123 by Pgp in all groups was faster in CD8+ T cells. All immunosuppressants and the specific Pgp inhibitor PSC833 diminished antigen-primed T-cell proliferation, especially CD8+ T-cell subset. Conclusions. Our data indicate that small molecules immunosuppressants, especially CsA, inhibit Pgp activity and T-cell function being the CD8+ T cells more susceptible to this effect. These findings support the importance of Pgp when designing combined immunosuppressive regimens. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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