scholarly journals Lactate potentiates differentiation and expansion of cytotoxic T cells

2019 ◽  
Author(s):  
Helene Rundqvist ◽  
Pedro Veliça ◽  
Laura Barbieri ◽  
Paulo A. Gameiro ◽  
Pedro P. Cunha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Progression ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Tumour Growth ◽  
Tumour Progression ◽  
Cytotoxic T Cells ◽  
Malignant Tumour ◽  
Dependent Manner

AbstractExercise has a range of effects on metabolism. In animal models, repeated exertion reduces malignant tumour progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effect of exercise on tumour progression is unclear, as are the cellular actors involved. We show here that exercise-induced reduction in tumour growth is dependent on CD8+ T cells and that lactate, which is produced at high levels during exertion, increases proliferative capacity and cytotoxicity of CD8+ T cells. We found that at elevated levels lactate is used as a fuel during T cell activation. We further found that injection of lactate into animals can reduce malignant tumour growth in a dose-and CD8+ T cell-dependent manner. These data demonstrate that lactate can act to increase the anti-tumour activity of cytotoxic T cells, and in so doing, reduce cancer progression.

Regulation of Tim-3 function by binding to phosphatidylserine

2021 ◽  
Vol 478 (22) ◽  
pp. 3999-4004
Author(s):  
Lawrence P. Kane
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Transmembrane Protein ◽  
Cytotoxic T Cells ◽  
Cross Presentation ◽  
First Time

Tim-3 is a transmembrane protein that is highly expressed on subsets of chronically stimulated CD4+ helper and CD8+ cytotoxic T cells, with more transient expression during acute activation and infection. Tim-3 is also constitutively expressed by multiple types of myeloid cells. Like other TIM family members, Tim-3 can bind to phosphatidylserine displayed by apoptotic cells, and this interaction has been shown to mediate uptake of such cells by dendritic cells and cross-presentation of antigens to CD8+ T cells. In contrast, how the recognition of PS by Tim-3 might regulate the function of Tim-3+ T cells is not known. In their recent paper, Lemmon and colleagues demonstrate for the first time that recognition of PS by Tim-3 leads to enhanced T cell activation.

scholarly journals 605 Systemically administered HER2-targeted ISACs provoke a rapid, local response that engages the innate and adaptive arms of the immune system to eradicate tumors in preclinical models

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A640-A640
Author(s):  
Heidi LeBlanc ◽  
Cecelia Pearson ◽  
Justin Kenkel ◽  
LIsa Blum ◽  
Po Ho ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Single Agent ◽  
Fold Increase ◽  
List Type ◽  
Dependent Manner ◽  
Activation Markers

BackgroundImmune-stimulating antibody conjugates (ISACs) covalently attach immune stimulants to tumor-targeting antibodies such as trastuzumab. We have shown that HER2-targeted TLR7/8 ISACs elicit robust myeloid activation and tumor eradication in a TLR- and Fc-dependent manner in trastuzumab-resistant and HER2-low models. Upon treatment with ISACs, T cell-mediated immunological memory extends to tumor antigens beyond HER2.1 Here we describe the ISAC mechanism of action in vivo that leads to eradication of tumors in mice.MethodsEstablished syngeneic rHER2- or xenograft HER2-expressing tumors treated with anti-HER2 ISACs or appropriate controls were assessed for gene expression by NanoString Pan-Cancer Immune Profiling panel comprising 750 genes related to tumor immune biology. Tumor cytokines were measured using MesoScale Discovery (MSD) technology, and immune cell infiltrates were assessed by immunohistochemistry (IHC). Anti-tumor efficacy was assessed after depletion of CD8+ T cells and phagocytes.ResultsWithin 24 hours of administration, HER2-directed ISACs induced robust, target-dependent activation of the immune system. In a syngeneic tumor model, 34% of the measurable genes were significantly upregulated after treatment with the rHER2-targeted ISAC vs 0.1% with the non-binding ISAC control. Similarly, 13% vs 0% of genes were upregulated in a xenograft model after HER2-targeted vs control ISAC treatment. In both models anti-HER2 ISAC treatment led to activation of pathways indicative of TLR7/8 agonism (e.g. IRF-7; type 1 interferons), and FcgR engagement (e.g. NF-kappaB associated genes). Cytokines and chemokines, including myeloid chemokines CCL2/3/4 and T cell chemokines CXCL9/10/11 were specifically upregulated in the tumors at the gene and protein level, indicating robust activation of myeloid cells following anti-HER2 ISAC treatment. Furthermore, in syngeneic tumors T cell activation markers (e.g. Granzyme B; IFN-gamma) were induced within 24 hours post treatment with an anti-rHER2 ISAC, and IHC at day 6 showed a 5-fold increase in CD11c+ cells. Control-treated tumors had sparse CD8+ T cells, whereas rHER2-targeted ISAC treatment led to ~3.5-fold increase in T cell frequency that shifted the tumor microenvironment from immunologically cold to hot. The recruitment of both phagocytes and CD8+ T cells was consequential, as depletion of either abrogated anti-tumor efficacy of the rHER2-targeted ISAC. Systemically delivered ISACs were well-tolerated.ConclusionsIn contrast to other immune therapies, such as anti-PDL1/PD1 and anti-CD40, systemically administered ISACs locally engage both the innate and adaptive arms of the immune system to eradicate tumors. The molecular and cellular phenotype associated with ISAC-mediated activation is being evaluated in the on-going BDC-1001 Phase I/II clinical trial.2ReferenceAckerman Set al, Poster# P756, SITC 20192. Phase 1/2 Study of BDC-1001 as a Single Agent and in Combination With Pembrolizumab in Patients With Advanced HER2-Expressing Solid Tumors; ClinicalTrials.gov (NCT04278144)

scholarly journals 4-1BB Costimulatory Signals Preferentially Induce CD8+ T Cell Proliferation and Lead to the Amplification In Vivo of Cytotoxic T Cell Responses

1997 ◽  
Vol 186 (1) ◽  
pp. 47-55 ◽  
Author(s):  
Walter W. Shuford ◽  
Kerry Klussman ◽  
Douglas D. Tritchler ◽  
Deryk T. Loo ◽  
Jan Chalupny ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Cytotoxic T Cell ◽  
Type I ◽  
Cytokine Analysis ◽  
Costimulatory Signals

The 4-1BB receptor is an inducible type I membrane protein and member of the tumor necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4+ and CD8+ T cells after antigen- or mitogen-induced activation. Cross-linking of 4-1BB and the T cell receptor (TCR) on activated T cells has been shown to deliver a costimulatory signal to T cells. Here, we expand upon previously published studies by demonstrating that CD8+ T cells when compared with CD4+ T cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB. In comparison, CD28-mediated costimulatory signals appear to function in a reciprocal manner to those induced through 4-1BB costimulation. In vivo examination of the effects of anti-4-1BB monoclonal antibodies (mAbs) on antigen-induced T cell activation have shown that the administration of epitope-specific anti-4-1BB mAbs amplified the generation of H-2d–specific cytotoxic T cells in a murine model of acute graft versus host disease (GVHD) and enhanced the rapidity of cardiac allograft or skin transplant rejection in mice. Cytokine analysis of in vitro activated CD4+ and CD8+ T cells revealed that anti-4-1BB costimulation markedly enhanced interferon-γ production by CD8+ T cells and that anti-4-1BB mediated proliferation of CD8+ T cells appears to be IL-2 independent. The results of these studies suggest that regulatory signals delivered by the 4-1BB receptor play an important role in the regulation of cytotoxic T cells in cellular immune responses to antigen.

scholarly journals pMHC affinity controls duration of CD8+ T cell–DC interactions and imprints timing of effector differentiation versus expansion

2016 ◽  
Vol 213 (12) ◽  
pp. 2811-2829 ◽  
Author(s):  
Aleksandra J. Ozga ◽  
Federica Moalli ◽  
Jun Abe ◽  
Jim Swoger ◽  
James Sharpe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Effector T Cells ◽  
Dependent Manner ◽  
Functional Avidity ◽  
High Affinity ◽  
Avidity Maturation

During adaptive immune responses, CD8+ T cells with low TCR affinities are released early into the circulation before high-affinity clones become dominant at later time points. How functional avidity maturation is orchestrated in lymphoid tissue and how low-affinity cells contribute to host protection remains unclear. In this study, we used intravital imaging of reactive lymph nodes (LNs) to show that T cells rapidly attached to dendritic cells irrespective of TCR affinity, whereas one day later, the duration of these stable interactions ceased progressively with lowering peptide major histocompatibility complex (pMHC) affinity. This correlated inversely BATF (basic leucine zipper transcription factor, ATF-like) and IRF4 (interferon-regulated factor 4) induction and timing of effector differentiation, as low affinity–primed T cells acquired cytotoxic activity earlier than high affinity–primed ones. After activation, low-affinity effector CD8+ T cells accumulated at efferent lymphatic vessels for egress, whereas high affinity–stimulated CD8+ T cells moved to interfollicular regions in a CXCR3-dependent manner for sustained pMHC stimulation and prolonged expansion. The early release of low-affinity effector T cells led to rapid target cell elimination outside reactive LNs. Our data provide a model for affinity-dependent spatiotemporal orchestration of CD8+ T cell activation inside LNs leading to functional avidity maturation and uncover a role for low-affinity effector T cells during early microbial containment.

scholarly journals Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8+ T-cell responses

2020 ◽  
Vol 4 (10) ◽  
pp. 2143-2157 ◽  
Author(s):  
Alak Manna ◽  
Timothy Kellett ◽  
Sonikpreet Aulakh ◽  
Laura J. Lewis-Tuffin ◽  
Navnita Dutta ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Lymphocytic Leukemia ◽  
Dependent Manner

Abstract Patients with chronic lymphocytic leukemia (CLL) are characterized by monoclonal expansion of CD5+CD23+CD27+CD19+κ/λ+ B lymphocytes and are clinically noted to have profound immune suppression. In these patients, it has been recently shown that a subset of B cells possesses regulatory functions and secretes high levels of interleukin 10 (IL-10). Our investigation identified that CLL cells with a CD19+CD24+CD38hi immunophenotype (B regulatory cell [Breg]–like CLL cells) produce high amounts of IL-10 and transforming growth factor β (TGF-β) and are capable of transforming naive T helper cells into CD4+CD25+FoxP3+ T regulatory cells (Tregs) in an IL-10/TGF-β-dependent manner. A strong correlation between the percentage of CD38+ CLL cells and Tregs was observed. CD38hi Tregs comprised more than 50% of Tregs in peripheral blood mononuclear cells (PBMCs) in patients with CLL. Anti-CD38 targeting agents resulted in lethality of both Breg-like CLL and Treg cells via apoptosis. Ex vivo, use of anti-CD38 monoclonal antibody (mAb) therapy was associated with a reduction in IL-10 and CLL patient-derived Tregs, but an increase in interferon-γ and proliferation of cytotoxic CD8+ T cells with an activated phenotype, which showed an improved ability to lyse patient-autologous CLL cells. Finally, effects of anti-CD38 mAb therapy were validated in a CLL–patient-derived xenograft model in vivo, which showed decreased percentage of Bregs, Tregs, and PD1+CD38hiCD8+ T cells, but increased Th17 and CD8+ T cells (vs vehicle). Altogether, our results demonstrate that targeting CD38 in CLL can modulate the tumor microenvironment; skewing T-cell populations from an immunosuppressive to immune-reactive milieu, thus promoting immune reconstitution for enhanced anti-CLL response.

scholarly journals Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19

2021 ◽  
Vol 6 (57) ◽  
pp. eabf7570
Author(s):  
Laura A. Vella ◽  
Josephine R. Giles ◽  
Amy E. Baxter ◽  
Derek A. Oldridge ◽  
Caroline Diorio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
Cell Activation ◽  
Vascular Complications ◽  
Adult Disease ◽  
Vasoactive Medication ◽  
Inflammatory Syndrome

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.

scholarly journals Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers

Nature ◽  
2021 ◽  
Author(s):  
Justina X. Caushi ◽  
Jiajia Zhang ◽  
Zhicheng Ji ◽  
Ajay Vaghasia ◽  
Boyang Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
T Cell Receptors ◽  
Tumour Microenvironment ◽  
Lung Cancers ◽  
Cell Receptors ◽  
Interleukin 7

AbstractPD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a ‘barcode’ to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein–Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.

scholarly journals Selective Bystander Proliferation of Memory CD4+ and CD8+ T Cells Upon NK T or T Cell Activation

2000 ◽  
Vol 165 (8) ◽  
pp. 4305-4311 ◽  
Author(s):  
Gérard Eberl ◽  
Pierre Brawand ◽  
H. Robson MacDonald
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation

scholarly journals CD28-B7 interactions allow the induction of CD8+ cytotoxic T lymphocytes in the absence of exogenous help.

1993 ◽  
Vol 177 (6) ◽  
pp. 1791-1796 ◽  
Author(s):  
F A Harding ◽  
J P Allison
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Histocompatibility Complex ◽  
Necessary And Sufficient ◽  
Additional Antigen

The activation requirements for the generation of CD8+ cytotoxic T cells (CTL) are poorly understood. Here we demonstrate that in the absence of exogenous help, a CD28-B7 interaction is necessary and sufficient for generation of class I major histocompatibility complex-specific CTL. Costimulation is required only during the inductive phase of the response, and not during the effector phase. Transfection of the CD28 counter receptor, B7, into nonstimulatory P815 cells confers the ability to elicit P815-specific CTL, and this response can be inhibited by anti-CD28 Fab or by the chimeric B7-binding protein CTLA4Ig. Anti-CD28 monoclonal antibody (mAb) can provide a costimulatory signal to CD8+ T cells when the costimulatory capacity of splenic stimulators is destroyed by chemical fixation. CD28-mediated signaling provokes the release of interleukin 2 (IL-2) from the CD8+ CTL precursors, as anti-CD28 mAb could be substituted for by the addition of IL-2, and an anti-IL-2 mAb can block the generation of anti-CD28-induced CTL. CD4+ cells are not involved in the costimulatory response in the systems examined. We conclude that CD8+ T cell activation requires two signals: an antigen-specific signal mediated by the T cell receptor, and an additional antigen nonspecific signal provided via a CD28-B7 interaction.

A Randomized Phase II Trial of Idiotype Vaccination and Adoptive Autologous T-Cell Transfer in Multiple Myeloma patients

Blood ◽  
2021 ◽  
Author(s):  
Muzaffar H Qazilbash ◽  
Neeraj Y Saini ◽  
Cha Soung-chul ◽  
Zhe Wang ◽  
Edward Stadtmauer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase Ii ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Phase Ii Trial ◽  
Ex Vivo ◽  
Vaccine Strategy ◽  
Randomized Phase Ii

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding anti-myeloma idiotype-keyhole limpet hemocyanin (Id-KLH) vaccine to vaccine-specific co-stimulated T cells. In this randomized, phase II trial, eligible patients received either the control (KLH only) or Id-KLH vaccine, an auto-transplant, vaccine-specific co-stimulated T-cells expanded ex-vivo, and two booster doses of the assigned vaccine. In 36 patients (20 in KLH, 16 in Id-KLH) enrolled, no dose-limiting toxicity was seen in either arm. At last evaluation, 6 (30%) and 8 (50%) had achieved complete remission in KLH-only and Id-KLH, respectively (p=0.22) and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; p=0.32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with KLH-only patients, there was a greater change in IR genes in T-cells in Id-KLH patients relative to baseline. Specifically, upregulation of genes associated with activation, induction of effector function, and generation of memory CD8+ T cells after Id-KLH, but not after KLH control vaccination, was observed. Similarly, responding patients across both arms were associated with upregulation of genes associated with T-cell activation. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of Id-KLH patients analyzed. In conclusion, in this combination immunotherapy approach, we observed a significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies.

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