Project description:Immune recognition of tumor-expressed antigens by cytotoxic CD8+ T lymphocytes is the foundation of adoptive T-cell therapy. However, therapy-induced selective pressure can sculpt the antigenicity of tumors resulting in the outgrowth of variants that have lost the target antigen. Interestingly, tumor relapse resulting from adoptive memory T cell transfer and boosting oncolytic viral vaccination can be prevented using Class I histone deacetylase inhibitor, MS-275. We demonstrate that concomitant drug delivery subverts the phenotype and suppressive function of tumor-infiltrating myeloid cells and reprograms them with the cytotoxic capacity to directly eliminate antigen-negative tumor cells. By enhancing the production of IFNγ within the tumor microenvironment, our data suggest that MS-275 modifies the local cytokine landscape in favor of antitumor myeloid cell polarization.
Project description:Transcriptional profiling of tumor-infiltrating antigen-presenting myeloid subsets and CD8 T cells in mice bearing MC38-OVA tumors treated with or without radiotherapy, αSIRPα, and/or αPD-1 treatment
Project description:The immunosuppressive microenvironment surrounding tumor cells represents a key cause of treatment failure. Therefore, immunotherapies aimed at reprogramming the immune system have largely spread in the past years. We employed gene transfer into hematopoietic stem and progenitor cells to selectively express anti-tumoral cytokines in tumor-infiltrating monocytes/macrophages. We show that Interferon-γ (IFNγ) reduced tumor progression in mouse models of B-cell acute lymphoblastic leukemia (B-ALL) and colorectal carcinoma (MC38). Its activity was dependent on the capacity of the immune system to respond to IFNγ and drove counter-selection of leukemia cells expressing surrogate antigens. Gene-based IFNγ delivery induced antigen presentation in the myeloid compartment and on leukemia cells, leading to a wave of T cell recruitment and activation, with enhanced clonal expansion of cytotoxic CD8+ T lymphocytes. The activity of IFNγ was further enhanced by either co-delivery of tumor necrosis factor α (TNFα) or by drugs blocking immunosuppressive escape pathways, with the potential to obtain durable responses.
Project description:The immune system can recognize and respond to tumors. However there are some conditions in which the genetic instability and heterogeneity of tumor cells leads to the development of variants that can escape the immune system. T cells have infiltrated inside many tumors (Tumor Infiltrating Lymphocytes or TILs), but generally these TILs have lost their functional capacity and are unable to eliminate tumor cells. We developed a model of autochthonous melanoma in mice that recapitulates some aspects of inflammatory melanoma in humans. These include a systemic Th2/Th17-oriented chronic inflammation, recruitment of immunosuppressive myeloid cells and acquisition by TILs of an M-bM-^@M-^\exhaustedM-bM-^@M-^] phenotype characterized by expression of receptors for multiple inhibitory molecules. To address the molecular bases for the M-bM-^@M-^\exhaustedM-bM-^@M-^] TILs phenotype, we performed transcriptomic analyses on sorted CD8 or T cells from the induced melanomas. These transcriptomes were compared to those of naM-CM-/ve CD8 T cells and of CD8 T cells immunized with a virus. 10 samples, 3 replicates for controls (untreated and infected with AdP1A), 4 replicates for TILs CD8 from melanoma
Project description:Epigenetic regulation plays a crucial role in the development and progression of cancer, including the regulation of antitumor immunity. The reversible nature of epigenetic modifications offers potential therapeutic avenues for cancer treatment. In particular, Histone deacetylase (HDAC) inhibitors (HDACi) have been shown to promote antitumor T cell immunity by regulating myeloid cell types, enhancing tumor antigen presentation, and increasing expression of chemokines. HDACi are currently being evaluated to determine whether they can increase the response rate of immune checkpoint inhibitors (ICIs) in cancer patients. While the potential direct effect of HDACi on T cells likely impacts antitumor immunity, little is known about how HDAC inhibition alters the transcriptomic profile of T cells. Here, we show that two clinical-stage HDACi profoundly impact gene expression and signaling networks in CD8+ and CD4+ T cells. Specifically, HDACi promoted T cell effector function by enhancing expression of TNFa and IFNg and increasing CD8+ T cell cytotoxicity. Consistently, in a murine tumor model, HDACi led to enrichment of CD8+ T cell subsets with high expression of effector molecules (Prf1, Ifng, Gzmk, Grmb) but also molecules associated with T cell exhaustion (Tox, Pdcd1, Lag3, Havcr2). HDACi further generated a TME dominated by myeloid cells with immune suppressive signatures. These results indicate that HDACi directly and favorably augment T cell effector function but also increase their exhaustion signal in the TME, which may add a layer of complexity for achieving clinical benefit in combination with ICIs.
Project description:Epigenetic regulation plays a crucial role in the development and progression of cancer, including the regulation of antitumor immunity. The reversible nature of epigenetic modifications offers potential therapeutic avenues for cancer treatment. In particular, Histone deacetylase (HDAC) inhibitors (HDACi) have been shown to promote antitumor T cell immunity by regulating myeloid cell types, enhancing tumor antigen presentation, and increasing expression of chemokines. HDACi are currently being evaluated to determine whether they can increase the response rate of immune checkpoint inhibitors (ICIs) in cancer patients. While the potential direct effect of HDACi on T cells likely impacts antitumor immunity, little is known about how HDAC inhibition alters the transcriptomic profile of T cells. Here, we show that two clinical-stage HDACi profoundly impact gene expression and signaling networks in CD8+ and CD4+ T cells. Specifically, HDACi promoted T cell effector function by enhancing expression of TNFa and IFNg and increasing CD8+ T cell cytotoxicity. Consistently, in a murine tumor model, HDACi led to enrichment of CD8+ T cell subsets with high expression of effector molecules (Prf1, Ifng, Gzmk, Grmb) but also molecules associated with T cell exhaustion (Tox, Pdcd1, Lag3, Havcr2). HDACi further generated a TME dominated by myeloid cells with immune suppressive signatures. These results indicate that HDACi directly and favorably augment T cell effector function but also increase their exhaustion signal in the TME, which may add a layer of complexity for achieving clinical benefit in combination with ICIs.
Project description:Resident and infiltrating myeloid cells are frequently reported to be tumor-promoting upon incidence of BCBM, but these cells are often poorly discriminated. We utilized scRNAseq to transcriptionally discriminate key immune cell populations and identify that microglia are predominantly pro-inflammatory upon BCBM initiation, and driven to an antigen presenting phenotype by infiltrating T cells.
