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Project description:Purpose: Epigenetic drug DNA methyltransferase inhibitors (DNMTis) are immunomodulating agents that may sensitize cancer cells to immune cell attack. However, it is still unclear how DNMTi affects cancer cells to the killing by immune cells. We therefore try to uncover the alternations of genomic DNA methylation, chromatin accessibility and transcriptomes after DNMTi treatment of cancer cells. Methods: Six human lung cancer cell lines (A549, H1299, CL1-0, CL1-5, H1792, PC9) treated without (Mock) or with 100 nM decitabine (DAC) for 72 hours followed by growing in drug-free medium for three days were subjected to mRNA-seq and Omni-ATAC-seq analyses. Results: mRNA-seq and ATAC-seq analyses reveal upregulation of actin and intermediate filament, and downregulation of microtubule modules by decitabine in human lung cancer cell lines. Conclusion: Decitabine primes lung cancer cells to γδ T cell-mediated killing through regulating cytoskeleton associated genes potentially involved in immune synapse formation.
2021-02-16 | GSE145663 | GEO
Project description:Epigenetic therapy strengthens immune synapses to potentiate susceptibility of lung cancer cells to adoptive γδ T cell therapy
| PRJNA607906 | ENA
Project description:Epigenetic therapy strengthens immune synapses to potentiate susceptibility of lung cancer cells to adoptive γδ T cell therapy [seq]
| PRJNA607909 | ENA
Project description:Ionizing radiation induces direct and indirect killing of cancer cells and for long has been considered as immunosuppressive. However, this concept has evolved over the past few years with the demonstration that irradiation can increase tumor immunogenicity and can actually favor the implementation of an immune response against tumor cells. Adoptive T-cell transfer (ACT) is also used to treat cancer and several studies have shown that the efficacy of this immunotherapy was enhanced when combined with radiation therapy. ?-Radioimmunotherapy (?-RIT) is a type of internal radiotherapy which is currently under development to treat disseminated tumors. ?-particles are indeed highly efficient to destroy small cluster of cancer cells with minimal impact on surrounding healthy tissues. We thus hypothesized that, in the setting of ?-RIT, an immunotherapy like ACT, could benefit from the immune context induced by irradiation. Hence, we decided to further investigate the possibilities to promote an efficient and long-lasting anti-tumor response by combining ?-RIT and ACT. To perform such study we set up a multiple myeloma murine model which express the tumor antigen CD138 and ovalbumine (OVA). Then we evaluated the therapeutic efficacy in the mice treated with ?-RIT, using an anti-CD138 antibody coupled to bismuth-213, followed by an adoptive transfer of OVA-specific CD8+ T cells (OT-I CD8+ T cells). We observed a significant tumor growth control and an improved survival in the animals treated with the combined treatment. These results demonstrate the efficacy of combining ?-RIT and ACT in the MM model we established.
| S-EPMC4476754 | biostudies-literature
Project description:Mast cells (MCs) are immune sentinels, but whether they also function as antigen-presenting cells (APCs) remains elusive. Using mouse models of MC deficiency, we report on MC-dependent recruitment and activation of multiple T cell subsets to the skin and draining lymph nodes (DLNs) during dengue virus (DENV) infection. Newly recruited and locally proliferating γδ T cells were the first T cell subset to respond to MC-driven inflammation, and their production of IFN-γ was MC dependent. MC-γδ T cell conjugates were observed consistently in infected peripheral tissues, suggesting a new role for MCs as nonconventional APCs for γδ T cells. MC-dependent γδ T cell activation and proliferation during DENV infection required T cell receptor (TCR) signaling and the nonconventional antigen presentation molecule endothelial cell protein C receptor (EPCR) on MCs. γδ T cells, not previously implicated in DENV host defense, killed infected targeted DCs and contributed to the clearance of DENV in vivo. We believe immune synapse formation between MCs and γδ T cells is a novel mechanism to induce specific and protective immunity at sites of viral infection.
| S-EPMC6391097 | biostudies-literature
Project description:γδ T cells are a distinct subgroup of T cells that bridge the innate and adaptive immune system and can attack cancer cells in an MHC-unrestricted manner. Trials of adoptive γδ T cell transfer in solid tumors have had limited success. Here, we show that DNA methyltransferase inhibitors (DNMTis) upregulate surface molecules on cancer cells related to γδ T cell activation using quantitative surface proteomics. DNMTi treatment of human lung cancer potentiates tumor lysis by ex vivo-expanded Vδ1-enriched γδ T cells. Mechanistically, DNMTi enhances immune synapse formation and mediates cytoskeletal reorganization via coordinated alterations of DNA methylation and chromatin accessibility. Genetic depletion of adhesion molecules or pharmacological inhibition of actin polymerization abolishes the potentiating effect of DNMTi. Clinically, the DNMTi-associated cytoskeleton signature stratifies lung cancer patients prognostically. These results support a combinatorial strategy of DNMTis and γδ T cell-based immunotherapy in lung cancer management.
| S-EPMC8042060 | biostudies-literature
Project description:Epigenetic therapy is a novel tumor therapeutic method and refers to the targeting of the aberrant epigenetic modifications presumably at cancer-related genes by chemicals which are epigenetic targeting drugs (ETDs). Not like in treating hematopoietic cancer, the clinical trials investigating the potential use of ETDs in the solid tumor is not encouraging. Instead, the curative effects of ETD delivered together with DNA targeting chemo drugs (DTDs) are quite promising according to our meta-analysis. To investigate the synergistic mechanism of ETD and DTD drug combination, the therapeutic effect was studied using both cell lines and mouse engrafted tumors. Mechanically we show that HDAC inhibitors and DNMT inhibitors are capable of increasing the chromatin accessibility to cisplatin (CP) and doxorubicin (Dox) through chromatin decompaction globally. Consequently, the combination of ETD and DTD enhances the DTD induced DNA damage and cell death. Engrafted tumors in SCID mice also show increased sensitivity to irradiation (IR) or CP when the tumors were pretreated by ETDs. Given the limited therapeutic effect of ETD alone, these results strongly suggest that the combination of DTD, including irradiation, and ETD treatment is a very promising choice in clinical solid tumor therapy.
| S-EPMC5481380 | biostudies-literature
Project description:Cell-based immunotherapy for lymphoid malignancies has gained increasing attention as patients develop resistance to conventional treatments. γδ T cells, which have major histocompatibility complex (MHC)-unrestricted lytic activity, have become a promising candidate population for adoptive cell transfer therapy. We previously established a stable condition for expanding γδ T cells by using anti-γδ T-cell receptor (TCR) antibody. In this study, we found that adoptive transfer of the expanded γδ T cells to Daudi lymphoma-bearing nude mice significantly prolonged the survival time of the mice and improved their living status. We further investigated the characteristics of these antibody-expanded γδ T cells compared to the more commonly used phosphoantigen-expanded γδ T cells and evaluated the feasibility of employing them in the treatment of lymphoid malignancies. Slow but sustained proliferation of human peripheral blood γδ T cells was observed upon stimulation with anti-γδ TCR antibody. Compared to phosphoantigen-stimulated γδ T cells, the antibody-expanded cells manifested similar functional phenotypes and cytotoxic activity towards lymphoma cell lines. It is noteworthy that the anti-γδ TCR antibody could expand both the Vδ1 and Vδ2 subsets of γδ T cells. The in vitro-expanded Vδ1 T cells displayed comparable tumour cell-killing activity to Vδ2 T cells. Importantly, owing to higher C-C chemokine receptor 4 (CCR4) and CCR8 expression, the Vδ1 T cells were more prone to infiltrate CCL17- or CCL22-expressing lymphomas than the Vδ2 T cells. Characterizing the peripheral blood γδ T cells from lymphoma patients further confirmed that the anti-γδ TCR antibody-expanded γδ T cells could be a more efficacious choice for the treatment of lymphoid malignancies than phosphoantigen-expanded γδ T cells.
| S-EPMC4002925 | biostudies-other
Project description:Impressive clinical benefit is seen in clinic with PD-1 inhibitors on portion of cancer patients. Yet, there remains an urgent need to develop effective synergizers to expand their clinical application. Tumor associated macrophage (TAM), a type of M2-polarized macrophage, eliminates or suppresses T cell mediated anti-tumor responses. Transforming TAMs into M1 macrophages is an attractive strategy of anti-tumor therapy. Here we conducted a high-throughput screening and found that Carfilzomib potently drove M2 macrophages to express M1 cytokines, phagocytose tumor cells and present antigens to T cells. Mechanistically, Carfilzomib elicited unfolded protein response (UPR), activated IRE1α to recruit TRAF2, and activated NF-κB to transcribe genes encoding M1 markers in M2 macrophages. In vivo, Carfilzomib effectively rewired tumor microenvironment through reprogramming TAMs into M1-like macrophages and shrank autochthonous lung cancers in transgenic mouse model. More importantly, Carfilzomib synergized with PD-1 antibody to almost completely regress autochthonous lung cancers. Given the safety profiles of Carfilzomib in clinic, our work suggested a potentially immediate application of combinational treatment with Carfilzomib and PD-1 inhibitors for patients with solid tumors.
| S-SCDT-EMM-2021-14502 | biostudies-other
Project description:Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/β-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC.
| S-EPMC5808406 | biostudies-literature