Project description:KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted therapies, immune checkpoint blockade and engineered T cells. In this study, we performed a systematic high throughput combinatorial drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib. Using bulk and single-cell RNA sequencing and immunophenotyping, we show that the combination therapy reprograms the immunosuppressive microenvironment and primes cytotoxic and memory T cells to infiltrate the tumors, thereby sensitizing mesenchymal PDAC to PD-L1 inhibition.
Project description:KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted therapies, immune checkpoint blockade and engineered T cells. In this study, we performed a systematic high throughput combinatorial drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi- kinase inhibitor nintedanib. Using single cell RNA sequencing and immunophenotyping, we show that the combination therapy reprograms the immunosuppressive microenvironment and primes cytotoxic and memory T cells to infiltrate the tumors, thereby sensitizing mesenchymal PDAC to PD-L1 inhibition.
Project description:IL-2/IL-15/IL-21-expanded TILs achieved complete tumor regression in a hypermutated glioblastoma patient, overcoming the immunosuppressive microenvironment. This case highlights a novel approach for treating gliomas using tailored adoptive cell therapy strategies.
Project description:IL-2/IL-15/IL-21-expanded TILs achieved complete tumor regression in a hypermutated glioblastoma patient, overcoming the immunosuppressive microenvironment. This case highlights a novel approach for treating gliomas using tailored adoptive cell therapy strategies.
Project description:IL-2/IL-15/IL-21-expanded TILs achieved complete tumor regression in a hypermutated glioblastoma patient, overcoming the immunosuppressive microenvironment. This case highlights a novel approach for treating gliomas using tailored adoptive cell therapy strategies.
Project description:KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted therapies, immune checkpoint blockade and engineered T cells. Here, we performed a systematic high throughput combinatorial drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib. This interaction targets KRAS-directed oncogenic signaling in the aggressive and therapy resistant non-glandular mesenchymal subtype of PDAC, driven by an allelic imbalance, increased gene-dosage and expression of oncogenic KRAS. Mechanistically, the combinatorial treatment induces cell cycle arrest and cell death and initiates an interferon response. Using single cell RNA sequencing and immunophenotyping, we show that the combination therapy reprograms the immunosuppressive microenvironment and primes cytotoxic and memory T cells to infiltrate the tumors, thereby sensitizing mesenchymal PDAC to PD-L1 inhibition. This work opens new avenues to target the therapy refractory mesenchymal PDAC subtype.
Project description:KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted therapies, immune checkpoint blockade and engineered T cells. Here, we performed a systematic high throughput combinatorial drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib. This interaction targets KRAS-directed oncogenic signaling in the aggressive and therapy resistant non-glandular mesenchymal subtype of PDAC, driven by an allelic imbalance, increased gene-dosage and expression of oncogenic KRAS. Mechanistically, the combinatorial treatment induces cell cycle arrest and cell death and initiates an interferon response. Using single cell RNA sequencing and immunophenotyping, we show that the combination therapy reprograms the immunosuppressive microenvironment and primes cytotoxic and memory T cells to infiltrate the tumors, thereby sensitizing mesenchymal PDAC to PD-L1 inhibition. This work opens new avenues to target the therapy refractory mesenchymal PDAC subtype.
Project description:Glioblastoma (GBM) is a malignancy with a complex tumour microenvironment (TME) dominated by glioblastoma stem cells (GSCs) and infiltrated by tumour-associated macrophages (TAMs), and exhibits aberrant metabolic pathways. Lactate is a critical glycolytic metabolite that promotes tumour progression; however, the mechanisms of lactate transport and lactylation in the TME of GBM remain elusive. Here we show that lactate is transported from TAMs to GSCs via MCT4/MCT1. TAMs provide lactate to GSCs, promoting GSC proliferation and inducing lactylation of the non-homologous end joining (NHEJ) protein KU70 at lysine 317 (K317), which inhibits cGAS-STING signaling and remodels the immunosuppressive TME. Inhibition of lactate transport or targeting the lactylation of KU70, in combination with the immune checkpoint blockade, demonstrates additive therapeutic benefits in immunocompetent xenograft models. This study unveils TAM-derived lactate and lactylation as critical regulators in GSCs to enforce an immunosuppressive microenvironment, opening avenues for developing combinatorial therapy for GBM.
Project description:Interleukin-34 (IL-34) is an alternative ligand to colony-stimulating factor-1 (CSF-1) for the CSF-1 receptor that acts as a key regulator of monocyte/macrophage lineage. In this study, we show that cancer cells-derived IL-34 mediates resistance to immune checkpoint blockade regardless of CSF-1 existence. In a therapeutic study of a programmed death-1 and cytotoxic T-lymphocyte-associated antigen-4 blocking monoclonal antibody, the expression of IL-34 in tumors was accompanied with limited benefits compared to IL-34 non-expressing tumors in various murine cancer models. Consistent with its immunosuppressive characteristics, the expression of IL-34 in tumors correlates with decreased frequencies of cellular (such as CD8+ and CD4+ T cells) and molecular (including various cytokines and chemokines) effectors at the tumor microenvironment. In addition, IL-34 blockade expands the M1-macrophage population. Then, a neutralizing antibody against IL-34 helped to reverse these effects and improved the therapeutic effects of the immune checkpoint blockade in combinatorial therapeutic models, including a patient-derived xenograft model of primary lung adenocarcinoma. Collectively, we revealed that tumor-derived IL-34 inhibits the efficacy of immune checkpoint blockade and proposed the utility of IL-34 blockade as a new strategy for cancer therapy.
