scholarly journals Macrophage-Mediated Subversion of Anti-Tumour Immunity

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 747 ◽  
Author(s):  
Valeria Quaranta ◽  
Michael C. Schmid
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tumour Progression ◽  
Immune Surveillance ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Tumour Immunity ◽  
Cell Recruitment ◽  
Clinical Benefits

Despite the incredible clinical benefits obtained by the use of immune checkpoint blockers (ICBs), resistance is still common for many types of cancer. Central for ICBs to work is activation and infiltration of cytotoxic CD8+ T cells following tumour-antigen recognition. However, it is now accepted that even in the case of immunogenic tumours, the effector functions of CD8+ T cells are highly compromised by the presence of an immunosuppressive tumour microenvironment (TME) at the tumour site. Tumour-associated macrophages (TAMs) are among the most abundant non-malignant stromal cell types within the TME and they are crucial drivers of tumour progression, metastasis and resistance to therapy. TAMs are able to regulate either directly or indirectly various aspects of tumour immunity, including T cell recruitment and functions. In this review we discuss the mechanisms by which TAMs subvert CD8+ T cell immune surveillance and how their targeting in combination with ICBs represents a very powerful therapeutic strategy.

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 T-Cell Gene Therapy in Cancer Immunotherapy: Why It Is No Longer Just CARs on The Road

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1588 ◽  
Author(s):  
Michael D. Crowther ◽  
Inge Marie Svane ◽  
Özcan Met
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Antigen Receptors ◽  
The Road ◽  
Multiple Cell ◽  
On The Road ◽  
Cell Gene

T-cells have a natural ability to fight cancer cells in the tumour microenvironment. Due to thymic selection and tissue-driven immunomodulation, these cancer-fighting T-cells are generally low in number and exhausted. One way to overcome these issues is to genetically alter T-cells to improve their effectiveness. This process can involve introducing a receptor that has high affinity for a tumour antigen, with two promising candidates known as chimeric-antigen receptors (CARs), or T-cell receptors (TCRs) with high tumour specificity. This review focuses on the editing of immune cells to introduce such novel receptors to improve immune responses to cancer. These new receptors redirect T-cells innate killing abilities to the appropriate target on cancer cells. CARs are modified receptors that recognise whole proteins on the surface of cancer cells. They have been shown to be very effective in haematological malignancies but have limited documented efficacy in solid cancers. TCRs recognise internal antigens and therefore enable targeting of a much wider range of antigens. TCRs require major histocompatibility complex (MHC) restriction but novel TCRs may have broader antigen recognition. Moreover, there are multiple cell types which can be used as targets to improve the “off-the-shelf” capabilities of these genetic engineering methods.

Defective T Cell Migration in Chronic Lymphocytic Leukemia Is Repaired by Lenalidomide

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3117-3117
Author(s):  
Alan G. Ramsay ◽  
Lena Svensson ◽  
Nancy Hogg ◽  
John G. Gribben
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Direct Contact ◽  
Immune Surveillance ◽  
Lymphocytic Leukemia ◽  
T Cell Migration

Abstract We have previously demonstrated that multiple gene expression abnormalities are induced in T cells from chronic lymphocytic leukemia (CLL) patients including defects within the actin cytoskeleton signaling pathways that control immune recognition and motility (Gullu et al. JCI, 2005). T cell immune surveillance requires rapid migratory responses and LFA-1 (CD11a/CD18; αLβ2) is a promigratory receptor that engages the cytoskeleton to control migration. We hypothesized that CLL T cells may exhibit dysfunctional migration in response to ICAM-1, the principal ligand for LFA-1. Using time lapse microscopy, we observed significantly reduced chemokine SDF-1 (CXCL12) induced migration on ICAM-1 of CLL CD4 and CD8 T cells compared to age-matched healthy donor T cells. Healthy T cells tracked for 45 min displayed a random course of migration with an average speed of ~ 8 μm/min, whereas CLL T cells were slower ~ 5 μm/min (n=14, ~ 30% reduction, p<0.01). We further postulated that direct contact of CLL tumor cells with healthy T cells would induce this migratory defect. Healthy CD4 or CD8 T cells were cocultured with either allogeneic CLL B cells or allogeneic healthy B cells and subsequently used in migration assays. Co-culture with CLL cells resulted in significantly reduced T cell migration compared with co-culture with healthy B cells (~ 44% reduction in migration, n=6, p<0.01). Evidence that direct contact was required to induce this migratory defect was shown when no effect was observed when cell-cell adhesion was prevented by pretreatment of CLL cells with anti-ICAM-1 blocking antibody prior to primary co-culture with healthy T cells. This cancer-induced migratory defect was repaired when CLL T cells were pretreated with the immunomodulatory drug Lenalidomide (1μM for 1hr). Treatment with this agent enhanced the migratory potential of CLL T cells to a speed comparable to untreated and treated healthy T cells. The finding that lenalidomide can restore rapid migration in patient T cells provides evidence that this agent may increase immune surveillance in CLL patients.

scholarly journals Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Min Chen ◽  
Kumar Felix ◽  
Jin Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Types ◽  
Activated T Cells ◽  
Ifn Γ

AbstractAfter stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be determined. Here we show that perforin deficiency in mice, together with the deletion of Fas in DCs (perforin−/−DC-Fas−/−), led to DC accumulation, uncontrolled T-cell activation, and IFN-γ production by CD8+ T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas−/− DCs induced over-activation and IFN-γ production in perforin−/− CD8+ T cells. Neutralization of IFN-γ prevented the spreading of inflammatory responses to different cell types and protected the survival of perforin−/−DC-Fas−/− mice. Our data suggest that perforin and Fas synergize in the maintenance of DC homeostasis to limit T cell activation, and prevent the initiation of an inflammatory cascade.

scholarly journals Intra-tumoral injection of caerin 1.1 and 1.9 peptides in vaccinated TC-1 tumour bearing mice with PD-1 blockade modulates macrophage heterogeneity and the activation of CD8+ T cells in the tumour microenvironment

2020 ◽  
Author(s):  
Guoying Ni ◽  
Xiaolian Wu ◽  
Ying Liu ◽  
Hejie Li ◽  
Shu Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Effector Memory ◽  
Proteomic Profiling ◽  
T Subsets ◽  
Cell Transcriptome

Abstract Development of a vaccine formula that alters the tumour-infiltrating lymphocytes to be more immune active against a tumour is key to the improvement of clinical responses to immunotherapy. Here, we demonstrate that, in conjunction with E7 antigen specific immunotherapy, and IL-10 and PD-1 blockade, intra-tumoral administration of caerin 1.1 and 1.9 peptides further improves the tumour microenvironment (TME) when compared with injection of a control peptide. We used single cell transcriptomics and mass spectrometry-based proteomics to quantify changes in cellular activity across different cell types within the TME. We show that the injection of caerin 1.1/1.9 increases immune activating macrophages and NK cells, while reducing immunosuppressive macrophages with M2 phenotype, and increased numbers of activated CD8+ T cells with higher populations of memory and effector-memory CD8+ T subsets. Proteomic profiling demonstrated activation of Stat1 modulated apoptosis and production of nitric oxide. Further, computational integration of the proteome with the single cell transcriptome was consistent with deactivation of immune suppressive B cell function following caerin 1.1 and 1.9 treatment.

scholarly journals Neoleukin-2 enhances anti-tumour immunity downstream of peptide vaccination targeted by an anti-MHC class II VHH

Open Biology ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 190235 ◽  
Author(s):  
Stephanie J. Crowley ◽  
Patrick T. Bruck ◽  
Md Aladdin Bhuiyan ◽  
Amelia Mitchell-Gears ◽  
Michael J. Walsh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Class Ii ◽  
Tumour Immunity ◽  
Tumour Rejection

Cancer-specific mutations can lead to peptides of unique sequence presented on MHC class I to CD8 T cells. These neoantigens can be potent tumour-rejection antigens, appear to be the driving force behind responsiveness to anti-CTLA-4 and anti-PD1/L1-based therapies and have been used to develop personalized vaccines. The platform for delivering neoantigen-based vaccines has varied, and further optimization of both platform and adjuvant will be necessary to achieve scalable vaccine products that are therapeutically effective at a reasonable cost. Here, we developed a platform for testing potential CD8 T cell tumour vaccine candidates. We used a high-affinity alpaca-derived VHH against MHC class II to deliver peptides to professional antigen-presenting cells. We show in vitro and in vivo that peptides derived from the model antigen ovalbumin are better able to activate naive ovalbumin-specific CD8 T cells when conjugated to an MHC class II-specific VHH when compared with an irrelevant control VHH. We then used the VHH-peptide platform to evaluate a panel of candidate neoantigens in vivo in a mouse model of pancreatic cancer. None of the candidate neoantigens tested led to protection from tumour challenge; however, we were able to show vaccine-induced CD8 T cell responses to a melanoma self-antigen that was augmented by combination therapy with the synthetic cytokine mimetic Neo2/15.

scholarly journals Cancer cell-expressed BTNL2 facilitates tumour immune escape via engagement with IL-17A-producing γδ T cells

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Yanyun Du ◽  
Qianwen Peng ◽  
Du Cheng ◽  
Ting Pan ◽  
Wanwei Sun ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Tumour Progression ◽  
Γδ T Cells ◽  
Suppressor Cells ◽  
Negative Regulator ◽  
Tumour Immunity

AbstractTherapeutic blockade of the immune checkpoint proteins programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has transformed cancer treatment. However, the overall response rate to these treatments is low, suggesting that immune checkpoint activation is not the only mechanism leading to dysfunctional anti-tumour immunity. Here we show that butyrophilin-like protein 2 (BTNL2) is a potent suppressor of the anti-tumour immune response. Antibody-mediated blockade of BTNL2 attenuates tumour progression in multiple in vivo murine tumour models, resulting in prolonged survival of tumour-bearing mice. Mechanistically, BTNL2 interacts with local γδ T cell populations to promote IL-17A production in the tumour microenvironment. Inhibition of BTNL2 reduces the number of tumour-infiltrating IL-17A-producing γδ T cells and myeloid-derived suppressor cells, while facilitating cytotoxic CD8+ T cell accumulation. Furthermore, we find high BTNL2 expression in several human tumour samples from highly prevalent cancer types, which negatively correlates with overall patient survival. Thus, our results suggest that BTNL2 is a negative regulator of anti-tumour immunity and a potential target for cancer immunotherapy.

scholarly journals The identity of human tissue-emigrant CD8+ T cells

2020 ◽  
Author(s):  
Marcus Buggert ◽  
Laura A. Vella ◽  
Son Nguyen ◽  
Vincent Wu ◽  
Takuya Sekine ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Surveillance ◽  
Integrated Approach ◽  
T Cell Subsets ◽  
Thoracic Duct Lymph ◽  
Lymphocyte Migration ◽  
Adaptive Immune ◽  
Duct Lymph

ABSTRACTLymphocyte migration is essential for human adaptive immune surveillance. However, our current understanding of this process is rudimentary, because most human studies to date have been restricted to immunological analyses of blood and various tissues. To address this issue, we used an integrated approach to characterize tissue-emigrant immune cells in thoracic duct lymph (TDL). In humans and non-human primates, lymphocytes were by far the most abundant immune lineage population in efferent lymph, and a vast majority of these lymphocytes were T cells. Cytolytic CD8+ T cell subsets were clonotypically discrete and selectively confined to the intravascular circulation, persisting for months after inhibition of S1P-dependent tissue egress by FTY-720. In contrast, non-cytolytic CD8+ T cell subsets with stem-like epigenetic and transcriptional signatures predominated in tissues and TDL. Collectively, these data provide an atlas of the migratory immune system and define the nature of tissue-emigrant CD8+ T cells that recirculate via TDL.

Inherent CD40L Expression Complements CD8+ T Cell Dependent Anti-Tumor Immunity

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4494-4494
Author(s):  
Andreas Thiel ◽  
Marco Frentsch ◽  
Regina Stark ◽  
Alberto Sada Japp ◽  
Joanna Listopad ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Cell Types ◽  
Cd8 T Cell ◽  
Novel Treatment ◽  
Cd40l Expression

Introduction & Objective Adoptive T cell therapy with tumor-specific CD8+ T cells is a promising treatment option for a variety of malignant diseases. However, it is unclear which subset of CD8+ T cells characterized by distinct functions is most suitable for achieving effective and durable anti tumor responses. So far CD8+ T cells have been considered to act predominantly as cytotoxic effector cells in cellular anti-tumor immunity. In this respect cytolytic molecules such as perforin and granzymes and apoptosis-inducing receptors of the tumor necrosis family such as FasL, TNFα and TRAIL have been regarded as major CD8+ T cell effector mechanisms. Methods & Results We here demonstrate in an experimental tumor model that CD40L, the key molecule for “immunological help”, is expressed by up to 50% of tumor-specific CD8+ T cells in B6 mice challenged with SV40 T antigen+ cancer cells. To study the influence of CD40L on anti-tumor CD8+ T cell immunity in vivo we challenged Rag1-/- mice with cancer cells and transferred wt or CD40L-/- CD8+ T cells. Transfer of wt CD8+ T cells prevented the establishment of a solid tumor, whereas injection of CD40L-/- CD8+ T cells alone or in addition with wt CD4+ T cells resulted in a non-controlled tumor development similar to non-treated tumors. The requirement of CD40L on CD8+ T cells for tumor rejection was further confirmed by injecting cancer cells in mice that lack CD40L expression only on mature CD8+ T cells. CD40Lflox x E8Icre mice were more susceptible to tumor formation than wt mice. Furthermore we demonstrated that CD8+ T-cell derived CD40L had to interact with CD40 on cancer cells, an eminent signal to induce apoptosis in various cancer cell types. Conclusion Our results reveal a crucial functional relevance of CD40L expressed by CD8+ T cells in anti-tumor immunity. Various cancer cell types express CD40 and its engagement induces pro-apoptotic or growth-inhibitory signals in a variety of cancer cells. Therefore CD40 agonists are recognized as promising agents for therapeutic interventions. We here introduce CD40L+ CD8+ memory T cells as a new major physiological source of CD40L, essential for rejection of tumors. Our data reveal that the presence or absence of CD40L+ CD8+ T cells represents a crucial element in control of CD40 expressing cancers disclosing novel treatment approaches in adoptive T-cell therapies novel treatment approaches. Disclosures: No relevant conflicts of interest to declare.

Chemotherapy to induce T-cell subpopulation changes in advanced breast cancer patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12562-e12562 ◽  
Author(s):  
Giuditta Comolli ◽  
Martina Torchio ◽  
Benvenuto Franceschetti ◽  
Irene Cassaniti ◽  
Ilario Rapposelli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Cd8 T Cells ◽  
Standard Dose ◽  
Cell Subpopulation ◽  
Breast Cancer Patients ◽  
Clinical Benefits ◽  
Pre Treatment

e12562 Background: Recent data suggest that some anti-cancer agents may generate a stimulation of the immune system that can account for additional clinical responses. In breast cancer (BC) the immunomodulation via chemotherapy (CT) opens possible clinical applications, but: a) the variability in the immune response requires a careful pt selection and b) monitoring immunocompetence in clinical routine still represents a technical challenge.Changes in sub-populations of cytotoxic (CD8+) T-cells (as reported in aging) are not well documented in cancer pts. Methods: We utilized multi-color immunophenotyping by flow cytometry (FCM) using a high-resolution whole-blood assay in 39 pts (median age 53; 34 - 74 yrs) with advanced BC undergoing first-line, standard-dose anthracycline/taxane-based CT and in 12 older healthy women, during a 6-months study, to analyze variations in CD8+ T-cells and the effects of CT on different T-cell sub-populations. Results: In all BC pts there was a consistent decrease in absolute numbers of lymphocytes, T-cells and CD8+ T-cells, starting from the first course and persisting during all the CT program. Among the T-cells, there was a lower CD8-/CD8+ ratio, persisting over 6 months, in pts compared to controls. The proportion of CD28-CD57+ cells also remained higher among pts throughout the sampling duration. The number of CD28+CD57- and CD28-CD5- cells decreased faster during CT than CD28+CD57+ and CD28-CD57+ cells, while only CD28-CD57- cells showed a significant reconstitutive capacity after 6 months.Anti-tumor CT in BC pts can produce clinical benefits also by restoring the responsiveness of T cells and by increasing the frequency and activation of tumor specific T-cells already present in blood before CT. Conclusions: Anthracycline/taxane-based CT is able to elicit changes in the pts immune system. These changes appeared to be pronounced in BC pts, with senescent CD8+ T-cells playing an important role. The pre-treatment condition was not restored after 6 months of CT. Multi-parameter FCM is a powerful tool for detailed analysis of the immune dysfunctions during CT and it will also help the development of combined schedules of CT plus new immunotherapeutic agents.

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