Interleukin-33 (IL-33), considered as an alarmin released upon tissue stress or damage, is a member of the IL-1 family and binds the ST2 receptor. First described as a potent initiator of type 2 ...immune responses through the activation of T helper 2 (T
2) cells and mast cells, IL-33 is now also known as an effective stimulator of T
1 immune cells, natural killer (NK) cells, iNKT cells, and CD8 T lymphocytes. Moreover, IL-33 was shown to play an important role in several cancers due to its pro and anti-tumorigenic functions. Currently, IL-33 is a possible inducer and prognostic marker of cancer development with a direct effect on tumor cells promoting tumorigenesis, proliferation, survival, and metastasis. IL-33 also promotes tumor growth and metastasis by remodeling the tumor microenvironment (TME) and inducing angiogenesis. IL-33 favors tumor progression through the immune system by inducing M2 macrophage polarization and tumor infiltration, and upon activation of immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) or regulatory T cells. The anti-tumor functions of IL-33 also depend on infiltrated immune cells displaying T
1 responses. This review therefore summarizes the dual role of this cytokine in cancer and suggests that new proposals for IL-33-based cancer immunotherapies should be considered with caution.
Cytomegalovirus (CMV) infection is responsible for significant morbidity and mortality in immunocompromised patients, namely solid organ and hematopoietic cell transplant recipients, and can induce ...congenital infection in neonates. There is currently an unmet need for new management and treatment strategies. Establishment of an anti‐CMV immune response is critical in order to control CMV infection. The two main human T cells involved in HCMV‐specific response are αβ and non‐Vγ9Vδ2 T cells that belong to γδ T cell compartment. CMV‐induced non‐Vγ9Vδ2 T cells harbor a specific clonal expansion and a phenotypic signature, and display effector functions against CMV. So far, only two main molecular mechanisms underlying CMV sensing have been identified. Non‐Vγ9Vδ2 T cells can be activated either by stress‐induced surface expression of the γδT cell receptor (TCR) ligand annexin A2, or by a multimolecular stress signature composed of the γδTCR ligand endothelial protein C receptor and co‐stimulatory signals such as the ICAM‐1‐LFA‐1 axis. All this basic knowledge can be harnessed to improve the clinical management of CMV infection in at‐risk patients. In particular, non‐Vγ9Vδ2 T cell monitoring could help better stratify the risk of infection and move forward a personalized medicine. Moreover, recent advances in cell therapy protocols open the way for a non‐Vγ9Vδ2 T cell therapy in immunocompromised patients.
Immune checkpoint blockade therapeutics, notably antibodies targeting the programmed death 1 (PD-1) receptor and its PD-L1 and PD-L2 ligands, are currently revolutionizing the treatment of cancer. ...For a sizeable fraction of patients with melanoma, lung, kidney and several other solid cancers, monoclonal antibodies that neutralize the interactions of the PD-1/PD-L1 complex allow the reconstitution of long-lasting antitumor immunity. In hematological malignancies this novel therapeutic strategy is far less documented, although promising clinical responses have been seen in refractory and relapsed Hodgkin lymphoma patients. This review describes our current knowledge of PD-1 and PD-L1 expression, as reported by immunohistochemical staining in both non-Hodgkin lymphoma cells and their surrounding immune cells. Here, we discuss the multiple intrinsic and extrinsic mechanisms by which both T and B cell lymphomas up-regulate the PD-1/PD-L1 axis, and review current knowledge about the prognostic significance of its immunohistochemical detection. This body of literature establishes the cell surface expression of PD-1/PD-L1 as a critical determinant for the identification of non-Hodgkin lymphoma patients eligible for immune checkpoint blockade therapies.
The tumor bulk is composed of a highly heterogeneous population of cancer cells, as well as a large variety of resident and infiltrating host cells, extracellular matrix proteins, and secreted ...proteins, collectively known as the tumor microenvironment (TME). The TME is essential for driving tumor development by promoting cancer cell survival, migration, metastasis, chemoresistance, and the ability to evade the immune system responses. Therapeutically targeting tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), regulatory T-cells (T-regs), and mesenchymal stromal/stem cells (MSCs) is likely to have an impact in cancer treatment. In this review, we focus on describing the normal physiological functions of each of these cell types and their behavior in the cancer setting. Relying on the specific surface markers and secreted molecules in this context, we review the potential targeting of these cells inducing their depletion, reprogramming, or differentiation, or inhibiting their pro-tumor functions or recruitment. Different approaches were developed for this targeting, namely, immunotherapies, vaccines, small interfering RNA, or small molecules.
T cells responding to persistent tumor or viral antigens progressively lose their functional properties, a feature known as exhaustion. This state is also characterized by cell-surface expression of ...multiple inhibitory immune checkpoint receptors (IRs). Cancer immunotherapy by immune checkpoint targeting has shown impressive clinical outcomes, but requires substantial improvement given the limited number of patients who benefit from the treatment. Targeting the mechanisms controlling immune checkpoint expression could represent a step towards this aim. Accumulating data indicate that this strategy can limit immune checkpoint expression, in some instances simultaneously inhibiting several immune checkpoints. This review discusses various mechanisms through which IRs are activated or regulated, and ways these mechanisms could be exploited to develop more effective future immunotherapies.
Expression of IRs is involved in the progressive exhaustion of T cells by abrogating their functions. By exploiting this Achilles’ heel, tumor cells have evolved mechanisms of resistance allowing their immune escape.Immune checkpoint blockade significantly improves the clinical outcome of cancer patients, but only a minority are durably cured.IR expression is controlled by several mechanisms, some of which simultaneously regulate several of these receptors. Such controls, operating at the transcriptional and the post-transcriptional levels, pave the way to highly innovative immunotherapeutic strategies that can improve the efficacy of cancer treatment.
Cancer remains a leading cause of death in the world. To overcome this problem, it is necessary to develop new analysis tools, in complementarity to existing ones, to enable the early diagnostic of ...the diseases, personalized treatment, and further fundamental cancer mechanisms understanding. In this context, microwave-based and millimeter-wave-based dielectric spectroscopy performed at the cellular and molecular levels is progressively emerging, as it permits the non-invasive and real-time probing of cells in their culture biological medium. The recent advances of this topic are given in this paper with a specific highlight of its various assets.
Most human blood γδ cells are cytolytic TCRVγ9Vδ2
+
lymphocytes with antitumor activity. They are currently investigated in several clinical trials of cancer immunotherapy but so far, their tumor ...infiltration has not been systematically explored across human cancers. Novel algorithms allowing the deconvolution of bulk tumor transcriptomes to find the relative proportions of infiltrating leucocytes, such as CIBERSORT, should be appropriate for this aim but in practice they fail to accurately recognize γδ T lymphocytes. Here, by implementing machine learning from microarray data, we first improved the computational identification of blood-derived TCRVγ9Vδ2
+
γδ lymphocytes and then applied this strategy to assess their abundance as tumor infiltrating lymphocytes (γδ TIL) in ∼10,000 cancer biopsies from 50 types of hematological and solid malignancies. We observed considerable inter-individual variation of TCRVγ9Vδ2
+
γδ TIL abundance both within each type and across the spectrum of cancers tested. We report their prominence in B cell-acute lymphoblastic leukemia (B-ALL), acute promyelocytic leukemia (M3-AML) and chronic myeloid leukemia (CML) as well as in inflammatory breast, prostate, esophagus, pancreas and lung carcinoma. Across all cancers, the abundance of αβ TILs and TCRVγ9Vδ2
+
γδ TILs did not correlate. αβ TIL abundance paralleled the mutational load of tumors and positively correlated with inflammation, infiltration of monocytes, macrophages and dendritic cells (DC), antigen processing and presentation, and cytolytic activity, in line with an association with a favorable outcome. In contrast, the abundance of TCRVγ9Vδ2
+
γδ TILs did not correlate with these hallmarks and was variably associated with outcome, suggesting that distinct contexts underlie TCRVγ9Vδ2
+
γδ TIL and αβ TIL mobilizations in cancer.
The high cytotoxic activity of Vγ9Vδ2 T lymphocytes against tumor cells makes them useful candidates in anticancer therapies. However, the molecular mechanism of their activation by phosphoantigens ...(PAgs) is not completely known. Many studies have depicted the mechanism of Vγ9Vδ2 T-cell activation by PAg-sensed accessory cells, such as immune presenting cells or tumor cells. In this study, we demonstrated that pure resting Vγ9Vδ2 T lymphocytes can self-activate through exogenous PAgs, involving their TCR and the butyrophilins BTN3A1 and BTN2A1. This is the first time that these three molecules, concurrently expressed at the plasma membrane of Vγ9Vδ2 T cells, have been shown to be involved together on the same and unique T cell during PAg activation. Moreover, the use of probucol to stimulate the inhibition of this self-activation prompted us to propose that ABCA-1 could be implicated in the transfer of exogenous PAgs inside Vγ9Vδ2 T cells before activating them through membrane clusters formed by γ9TCR, BTN3A1 and BTN2A1. The self-activation of Vγ9Vδ2 T cells, which leads to self-killing, can therefore participate in the failure of γδ T cell-based therapies with exogenous PAgs and should be taken into account.
γδ T lymphocytes represent ∼1% of human peripheral blood mononuclear cells and even more cells in most tissues of vertebrates. Although they have important anticancer functions, most current ...single-cell RNA sequencing (scRNA-seq) studies do not identify γδ T lymphocytes because their transcriptomes at the single-cell level are unknown. Here we show that high-resolution clustering of large scRNA-seq datasets and a combination of gene signatures allow the specific detection of human γδ T lymphocytes and identification of their T cell receptor (TCR)Vδ1 and TCRVδ2 subsets in large datasets from complex cell mixtures. In t-distributed stochastic neighbor embedding plots from blood and tumor samples, the few γδ T lymphocytes appear collectively embedded between cytotoxic CD8 T and NK cells. Their TCRVδ1 and TCRVδ2 subsets formclose yet distinct subclusters, respectively neighboring NK and CD8 T cells because of expression of shared and distinct cytotoxic maturation genes. Similar pseudotime maturation trajectories of TCRVδ1 and TCRVδ2 γδ T lymphocytes were discovered, unveiling in both subsets an unattended pool of terminally differentiated effector memory cells with preserved proliferative capacity, a finding confirmed by in vitro proliferation assays. Overall, the single-cell transcriptomes of thousands of individual γδ T lymphocytes from different CMV⁺ and CMV⁻ donors reflect cytotoxic maturation stages driven by the immunological history of donors. This landmark study establishes the rationale for identification, subtyping, and deep characterization of human γδ T lymphocytes in further scRNA-seq studies of complex tissues in physiological and disease conditions.
Angioimmunoblastic T-cell lymphoma (AITL) is a malignancy with very poor survival outcome, in urgent need of more specific therapeutic strategies. The drivers of malignancy in this disease are CD4
...follicular helper T cells (Tfh). The metabolism of these malignant Tfh cells was not yet elucidated. Therefore, we decided to identify their metabolic requirements with the objective to propose a novel therapeutic option.
To reveal the prominent metabolic pathways used by the AITL lymphoma cells, we relied on metabolomic and proteomic analysis of murine AITL (mAITL) T cells isolated from our established mAITL model. We confirmed these results using AITL patient and healthy T cell expression data.
Strikingly, the mAITL Tfh cells were highly dependent on the second branch of the Kennedy pathway, the choline lipid pathway, responsible for the production of the major membrane constituent phosphatidylcholine. Moreover, gene expression data from Tfh cells isolated from AITL patient tumors, confirmed the upregulation of the choline lipid pathway. Several enzymes involved in this pathway such as choline kinase, catalyzing the first step in the phosphatidylcholine pathway, are upregulated in multiple tumors other than AITL. Here we showed that treatment of our mAITL preclinical mouse model with a fatty acid oxydation inhibitor, significantly increased their survival and even reverted the exhausted CD8 T cells in the tumor into potent cytotoxic anti-tumor cells. Specific inhibition of Chokα confirmed the importance of the phosphatidylcholine production pathway in neoplastic CD4 + T cells, nearly eradicating mAITL Tfh cells from the tumors. Finally, the same inhibitor induced in human AITL lymphoma biopsies cell death of the majority of the hAITL PD-1
neoplastic cells.
Our results suggest that interfering with choline metabolism in AITL reveals a specific metabolic vulnerability and might represent a new therapeutic strategy for these patients.
PDF
