T-cell tumour exclusion and immunotherapy resistance: a role for CAF targeting.
Ontology highlight
ABSTRACT:
SUBMITTER: Hanley CJ
PROVIDER: S-EPMC7591574 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
T-cell tumour exclusion and immunotherapy resistance: a role for CAF targeting.
Hanley Christopher J CJ Thomas Gareth J GJ
British journal of cancer 20200824 9
Recent studies have highlighted a major role for cancer-associated fibroblasts (CAFs) in promoting immunotherapy resistance by excluding T cells from tumours. Recently, we showed that CAFs can be effectively targeted by inhibiting the enzyme NOX4; this 'normalises' CAFs and overcomes immunotherapy resistance. Here we discuss our study and other strategies for CAF targeting. ...[more]
Similar Datasets
Project description:T cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-α (SIRPα), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRPα-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRPα, and not SIRPγ/CD47, in humans remains unknown. We report a potent synergy between selective SIRPα blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRPα blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRPα/SIRPγ blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRPα inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors.
| S-EPMC7598080 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs), although promising, have variable benefit in head and neck cancer (HNC). We noted that tumor galectin-1 (Gal1) levels were inversely correlated with treatment response and survival in patients with HNC who were treated with ICIs. Using multiple HNC mouse models, we show that tumor-secreted Gal1 mediates immune evasion by preventing T cell migration into the tumor. Mechanistically, Gal1 reprograms the tumor endothelium to upregulate cell-surface programmed death ligand 1 (PD-L1) and galectin-9. Using genetic and pharmacological approaches, we show that Gal1 blockade increases intratumoral T cell infiltration, leading to a better response to anti-PD1 therapy with or without radiotherapy. Our study reveals the function of Gal1 in transforming the tumor endothelium into an immune-suppressive barrier and that its inhibition synergizes with ICIs.
| S-EPMC6877340 | biostudies-literature
Project description:Tumour cells do not exist as isolated entities. Instead, they are surrounded by a variety of cells and extracellular matrix, which form the tumour microenvironment (TME). The interaction between cancer cells and their microenvironment is increasingly acknowledged as essential in dictating the outcome of the patients. The TME includes everything that surrounds tumour cells and is often highjacked by the latter to promote their growth, invasion, and immune escape. Immune cells and cancer-associated fibroblasts (CAFs) are essential components of the TME, and there is increasing evidence that their interaction constitutes a major player not only for tumour progression but also for therapy response.Recent work in the field of immuno-oncology resulted in the development of novel therapies that aim at activating immune cells against cancer cells to eliminate them. Despite their unprecedented success, the lack of response from a large portion of patients highlights the need for further progress and improvement. To achieve its ultimate goal, the interaction between cancer cells and the TME needs to be studied in-depth to allow the targeting of mechanisms that are involved in resistance or refractoriness to therapy. Moreover, predictive and prognostic biomarkers for patient stratification are still missing. In this review, we focus on and highlight the complexity of CAFs within the TME and how their interaction, particularly with immune cells, can contribute to treatment failure. We further discuss how this crosstalk can be further dissected and which strategies are currently used to target them.
| S-EPMC10121542 | biostudies-literature
Project description:Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignant tumours typically caused by alcohol and tobacco consumption, although an increasing number of HNSCC arise due to persistent infection with high-risk human papilloma virus (HPV). The treatment of HNSCC remains challenging, and the first-line setting is focused on surgery and chemoradiotherapy. A substantial proportion of HNSCC patients die from their disease, especially those with recurrent and metastatic disease. Among factors linked with good outcome, immune cell infiltration appears to have a major role. HPV-driven HNSCC are often T-cell rich, reflecting the presence of HPV antigens that are immunogenic. Tumour-associated antigens that are shared between patients or that are unique to an individual person may also induce varying degrees of immune response; studying these is important for the understanding of the interaction between the host immune system and the cancer. The resulting knowledge is critical for the design of better immunotherapies. Key questions are: Which antigens lead to an adaptive immune response in the tumour? Which of these are exploitable for immunotherapy? Here, we review the current thinking regarding tumour antigens in HNSCC and what has been learned from early phase clinical trials.
| S-EPMC7564543 | biostudies-literature
Project description:Immune checkpoint therapies (ICT) can reinvigorate the effector functions of anti-tumour T cells, improving cancer patient outcomes. Anti-tumour T cells are initially formed during their first contact (priming) with tumour antigens by antigen-presenting cells (APCs). Unfortunately, many patients are refractory to ICT because their tumours are considered to be 'cold' tumours-i.e., they do not allow the generation of T cells (so-called 'desert' tumours) or the infiltration of existing anti-tumour T cells (T-cell-excluded tumours). Desert tumours disturb antigen processing and priming of T cells by targeting APCs with suppressive tumour factors derived from their genetic instabilities. In contrast, T-cell-excluded tumours are characterised by blocking effective anti-tumour T lymphocytes infiltrating cancer masses by obstacles, such as fibrosis and tumour-cell-induced immunosuppression. This review delves into critical mechanisms by which cancer cells induce T-cell 'desertification' and 'exclusion' in ICT refractory tumours. Filling the gaps in our knowledge regarding these pro-tumoral mechanisms will aid researchers in developing novel class immunotherapies that aim at restoring T-cell generation with more efficient priming by APCs and leukocyte tumour trafficking. Such developments are expected to unleash the clinical benefit of ICT in refractory patients.
| S-EPMC10575907 | biostudies-literature
Project description:Tumour microenvironment is a complex ecosystem in which myeloid cells are the most abundant immune elements. This cell compartment is composed by different cell types, including neutrophils, macrophages, dendritic cells, and monocytes but also unexpected cell populations with immunosuppressive and pro-tumour roles. Indeed, the release of tumour-derived factors influences physiological haematopoiesis producing unconventional cells with immunosuppressive and tolerogenic functions such as myeloid-derived suppressor cells. These pro-tumour myeloid cell populations not only support immune escape directly but also assist tumour invasion trough non-immunological activities. It is therefore not surprising that these cell subsets considerably impact in tumour progression and cancer therapy resistance, including immunotherapy, and are being investigated as potential targets for developing a new era of cancer therapy. In this review, we discuss emerging strategies able to modulate the functional activity of these tumour-supporting myeloid cells subverting their accumulation, recruitment, survival, and functions. These innovative approaches will help develop innovative, or improve existing, cancer treatments.
| S-EPMC9513014 | biostudies-literature
Project description:Cancer treatment by immune checkpoint blockade (ICB) can bring long-lasting clinical benefits, but only a fraction of patients respond to treatment. To predict ICB response, we developed TIDE, a computational method to model two primary mechanisms of tumor immune evasion: the induction of T cell dysfunction in tumors with high infiltration of cytotoxic T lymphocytes (CTL) and the prevention of T cell infiltration in tumors with low CTL level. We identified signatures of T cell dysfunction from large tumor cohorts by testing how the expression of each gene in tumors interacts with the CTL infiltration level to influence patient survival. We also modeled factors that exclude T cell infiltration into tumors using expression signatures from immunosuppressive cells. Using this framework and pre-treatment RNA-Seq or NanoString tumor expression profiles, TIDE predicted the outcome of melanoma patients treated with first-line anti-PD1 or anti-CTLA4 more accurately than other biomarkers such as PD-L1 level and mutation load. TIDE also revealed new candidate ICB resistance regulators, such as SERPINB9, demonstrating utility for immunotherapy research.
| S-EPMC6487502 | biostudies-literature
Project description:BackgroundVinflunine (VFL) is a microtubule-targeting drug that suppresses microtubule dynamics, showing anti-metastatic properties both in vitro and in living cancer cells. An increasing body of evidence underlines the influence of the microtubules dynamics on the cadherin-dependent cell-cell adhesions. E-cadherin is a marker of epithelial-to-mesenchymal transition (EMT) and a tumour suppressor; its reduced levels in carcinoma are associated with poor prognosis. In this report, we investigate the role of VFL on cell-cell adhesions in bladder epithelial tumour cells.MethodsHuman bladder epithelial tumour cell lines HT1376, 5637, SW780, T24 and UMUC3 were used to analyse cadherin-dependent cell-cell adhesions under VFL treatment. VFL effect on growth inhibition was measured by using a MTT colorimetric cell viability assay. Western blot, immunofluorescence and transmission electron microscopy analyses were performed to assess the roles of VFL effect on cell-cell adhesions, epithelial-to-mesenchymal markers and apoptosis. The role of the proteasome in controlling cell-cell adhesion was studied using the proteasome inhibitor MG132.ResultsWe show that VFL induces cell death in bladder cancer cells and activates epithelial differentiation of the remaining living cells, leading to an increase of E-cadherin-dependent cell-cell adhesion and a reduction of mesenchymal markers, such as N-cadherin or vimentin. Moreover, while E-cadherin is increased, the levels of Hakai, an E3 ubiquitin-ligase for E-cadherin, were significantly reduced in presence of VFL. In 5637, this reduction on Hakai expression was blocked by MG132 proteasome inhibitor, indicating that the proteasome pathway could be one of the molecular mechanisms involved in its degradation.ConclusionsOur findings underscore a critical function for VFL in cell-cell adhesions of epithelial bladder tumour cells, suggesting a novel molecular mechanism by which VFL may impact upon EMT and metastasis.
| S-EPMC4107965 | biostudies-literature
Project description:BackgroundThere is an urgent need for new approaches to deliver bioactive molecules to cancer cells efficiently and specifically.MethodsHere we fuse the cancer cell nuclear targeting module of the Chicken Anaemia Virus Apoptin protein to the core histones H2B and H3 and utilise them in transfection, protein transduction and DNA binding assays.ResultsWe found subsequent nuclear accumulation of these proteins to be 2-3 fold higher in tumour compared to normal cells in transfected isogenic human osteosarcoma and breast tumour progression models. This represents the first demonstration of enhanced nuclear targeting by Apoptin in a tumour progression model, and its functionality in a heterologous protein context. Excitingly, we found that the innate transduction ability of histones could be exploited in combination with the Apoptin nuclear targeting module to effect an overall 13-fold higher delivery of protein to osteosarcoma cancer cell nuclei compared to their isogenic normal counterparts.ConclusionsThis is the first report of cancer-cell specificity by a cell penetrating protein, with important implications for the use of protein transduction as a vehicle for gene/drug delivery in the future, and in particular in the development of highly specific and effective anti-cancer agents.
| S-EPMC4342815 | biostudies-literature
Project description:BackgroundImmunotherapy has emerged as a crucial treatment modality for solid tumours, yet tumours often evade immune surveillance. There is an imperative to uncover novel immune regulators that can boost tumour immunogenicity and increase the efficacy of immune checkpoint blockade (ICB) therapy. Epigenetic regulators play critical roles in tumour microenvironment remodelling, and N6-methyladenosine (m6A) is known to be involved in tumourigenesis. However, the role of m6A in regulating T-cell function and enhancing anti-tumour immunity remains unexplored.MethodsSeveral cancer cell lines were treated with STM2457, an enzymatic inhibitor of RNA m6A methyltransferase METTL3, and explored the transcriptome changes with RNA sequencing (RNA-seq). We then utilised mouse melanoma (B16) and mouse colorectal adenocarcinoma (MC38) models to investigate the effects of METTL3 inhibition on immunotherapy, and analysed the dynamics of the tumour microenvironment via single-cell RNA-seq (scRNA-seq). Furthermore, in vitro and in vivo T-cell cytotoxicity killing assay and CRISPR Cas9-mediated m6A reader YTHDF1-3 knockout in B16 were performed to assess the role and the molecular mechanism of RNA m6A in tumour killing. Finally, the efficacy of METTL3 inhibition was also tested on human melanoma model (A375) and human T cells.ResultsWe demonstrate that inhibiting METTL3 augments tumour immunogenicity and sustains T-cell function, thereby enhancing responsiveness to ICB therapy. Mechanistically, METTL3 inhibition triggers an interferon response within tumour cells, amplifying the anti-tumour immune response, along with deletion of the m6A reader protein YTHDF2 in tumours inhibiting major histocompatibility complex (MHC)-I degradation. Remarkably, these anti-tumour effects are reliant on the immune system. Specifically, METTL3 inhibition enhances interferon-gamma (IFNγ) and granzyme B (GzmB) expression, thereby strengthening T-cell killing ability, and concurrently dampening the expression of exhaustion-related genes.ConclusionTargeting METTL3 enhances anti-tumour immunity by boosting T-cell cytotoxicity and reversing T-cell exhaustion. Our study positions METTL3 as an epigenetic checkpoint, highlighting the potential of targeting METTL3 to invigorate intrinsic anti-tumour defenses and overcome immune resistance.Key pointsTargeting METTL3 augments tumour cell immunogenicity and sustains T-cell function. T cell with METTL3 inhibition can reverse T-cell exhaustion, and promote expression of IFNγ and GzmB, thereby enhancing cytotoxicity in anti-PD-1 therapy. YTHDF2 deletion in tumours prolong the lifespan of MHC-I mRNAs.
| S-EPMC11578931 | biostudies-literature