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Combining anti-PD1 and vorinostat improves anti-tumor treatment in IDH-mutant brain tumors

ABSTRACT: Enhancer RNA (eRNA) is critical element with highly specific pattern in regulatory network across infiltrated immune cells. Herein we developed eRNA immunotherapy signature (eRIS) based on these eRNAs which significantly connected with anti-tumor immune cells. The eRIS was highly correlated with objective response rate (ORR) to immune checkpoint blockade (ICB) treatment, and was significantly increased in these patients who benefit from ICB treatment. By integrating with pharmacogenomics datasets, we screened hundreds of eRIS associated anti-cancer drugs, which showed potential in improving immunotherapy with cancer type or subtype-specific specific manner. We further characterized one drug, the HDAC inhibitor vorinostat, in isocitrate dehydrogenase mutant gliomas, and found Combining vorinostat with anti-PD-1 could decrease tumor size and increase survival time in vivo by enhancing abundance of anti-tumor immune cells. We further provided eRIS markers which showed strong capacity of eRIS in predicting immunotherapy response in clinical samples or animal models. Our study revealed the potential utility of eRIS to improve immunotherapy response by identifying combinational drugs, that provide novel insights to benefit patients in certain cancer or subtypes.

ORGANISM(S): Mus musculus

PROVIDER: GSE248513 | GEO | 2024/05/01

REPOSITORIES: GEO

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Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy [SZ14]

Project description:Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX-2/PGE2/EP2-4 pathway with widely used non-steroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to harness the heterogeneity in treatment outcome and distinguish responders from non-responders shortly following treatment. Deep cellular and molecular tumor profiling revealed acute IFN-γ-driven tumor remodeling in responder mice that was also associated with patient benefit to ICB. Crucially, monotherapy with COX-2 inhibitors or EP2-4 PGE2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of T cells with enhanced effector function. Inhibition of the COX-2/PGE2 pathway in patient-derived tumor fragments from multiple patients and cancer types revealed a similar shift in the tumor inflammatory environment to favor T cell activation. Our findings establish the COX-2/PGE2/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to switch the tumor inflammatory profile from cold to hot and enhance the efficacy of immunotherapy.

2021-09-13 | GSE160788 | GEO

Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy [SZ9]

2021-09-13 | GSE160785 | GEO

Immunologic and clinical activity to ICB combinations in DAPPER Leiomyosarcoma cohort

Project description:Non-inflamed (cold) tumors such as leiomyosarcoma (LMS) do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis-, or poly-ADP ribose polymerase (PARP) inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pre-treated LMS patients.

2024-01-01 | E-MTAB-12922 | biostudies-arrayexpress

Comprehensive testing of chemotherapy and immune checkpoint blockade in preclinical cancer models identifies additive combinations

Project description:Background: Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA 4) and the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) are now a treatment option for multiple cancer types. However, as a monotherapy, objective responses only occur in a minority of patients. Chemotherapy is widely used in combination with immune checkpoint blockade (ICB). Although a variety of isolated immunostimulatory effects have been reported for several classes of chemotherapeutics, it is unclear which chemotherapeutics provide the most benefit when combined with ICB. Methods: We investigated 10 chemotherapies from the main canonical classes dosed at the clinically relevant maximum tolerated dose in combination with anti CTLA-4/anti-PD-L1 ICB. We screened these chemo-immunotherapy combinations in two murine mesothelioma models from two different genetic backgrounds, and identified chemotherapies that produced additive, neutral or antagonistic effects when combined with ICB. Using flow cytometry and bulk RNAseq, we characterized the tumor immune milieu in additive chemo-immunotherapy combinations. Results: 5-fluorouracil (5-FU) or cisplatin were additive when combined with ICB while vinorelbine and etoposide provided no additional benefit when combined with ICB. The combination of 5-FU with ICB augmented an inflammatory tumor microenvironment with markedly increased CD8+ T cell activation and upregulation of IFN , TNF and IL-1β signaling. The effective anti tumor immune response of 5-FU chemo-immunotherapy was dependent on CD8+ T cells but was unaffected when TNF or IL 1β cytokine signaling pathways were blocked. Conclusions: Our study identified additive and non-additive chemotherapy/ICB combinations and suggests a possible role for increased inflammation in the tumor microenvironment as a basis for effective combination therapy.

2022-05-02 | GSE188481 | GEO

Expression profile comparison of enriched bone marrow-derived tumor associated macrophages, tumor-associated alveolar macrophages, CD4 T cells, and total tumor-derived cells in lung cancer models with or without anti-PD1 and anti-VEGFA/ANGPT2 treatments.

Project description:Immune checkpoint blockade (ICB) with PD1 or PDL1 antibodies has been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of the patients respond and sustained remissions are rare. Both chemotherapy and anti-angiogenic drugs may improve tumor response to ICB in mouse models and patients with cancer. Here, we used genetically engineered mouse models of KrasG12D/p53null NSCLC, including a mismatch repair-deficient variant (KrasG12D/p53null/Msh2null) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, anti-angiogenic therapy, and chemotherapy. Anti-angiogenic blockade of VEGFA and angiopoietin-2 markedly slowed progression of established tumors but, contrary to findings in other mouse cancer models, addition of a PD1 or PDL1 antibody was not beneficial and even accelerated progression of some of the tumors. We found that anti-angiogenic treatment facilitated tumor infiltration by PD1+ regulatory T cells (T-regs), which were more efficiently targeted by the PD1 antibody than CD8+ T cells. Both tumor-associated macrophages (TAMs) of bone-marrow origin, which are CSF1R-dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establishing a TGFB-rich tumor microenvironment that supported PD1+ T-regs. Dual TAM targeting with a combination of cisplatin and a CSF1R inhibitor fully abated T-regs, redirected the PD1 antibody to CD8+ T cells, and improved the efficacy of anti-angiogenic immunotherapy, achieving regression of the majority of the tumors.

2021-08-15 | GSE169194 | GEO

Treating ICB-resistant glioma with anti-CD40 and mitotic spindle checkpoint controller BAL101553 (lisavanbulin)

Project description:drugs targeting mitosis might affect the tumor microenvironment and sensitize cancer cells to immunotherapy. BAL101553 monotherapy increased survival in immune checkpoint blockade–resistant SB28 glioblastoma tumors and synergized with anti-CD40 antibody

2021-10-23 | GSE186302 | GEO

Vorinostat treatment of PPS-ICBR cells

Project description:We generated immune checkpoint blockade resistant cell lines from a prostate tumor driven by Probasin-Cre Pten/P53/Smad4 loxp deletion, through serial implantation and ICB treatment. We then wanted to explore whether gene expression changes associated with resistance to immune checkpoint blockade could be reversed by treating ICB resistant cells with the pan-HDAC inhibitor Vorinostat. We used a microarray to determine gene expression changes caused by Vorinostat treatment in these cells with biological duplicates.

2024-02-13 | GSE205469 | GEO

A ketogenic diet can revert acquired resistance to immunotherapy in prostate cancer through β-hydroxybutyrate-mediated inhibition of histone deacetylases

Project description:Prostate cancer is the second leading cause of cancer deaths in men in the US. In the past decade, immune checkpoint blockade (ICB) drugs targeting programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) have revolutionized the field of cancer therapeutics, but the objective response rate in prostate cancers is in the low single digits. A major complicating issue is that immunotherapies can have significant adverse effects, so there is a clinical need for novel combinatorial strategies that do not involve additional or compounding adverse effects. We developed a model system of advanced prostate cancer that has acquired resistance to ICB therapy. The PD-1 resistant sublines showed strong downregulation of the mouse major histocompatibility complex (MHC-I), which was reversed by treating cells with either the pan-histone deacetylase (HDAC) inhibitor Vorinostat or β-hydroxybutyrate. When mice bearing these ICB resistant tumor are treated with either Vorinostat, with a cyclical ketogenic diet (CKD), or with a 1,3-butanediol diet (BD), tumors are resensitized to ICB therapy. We analyzed changes in the tumor immune microenvironment and showed that this effect is driven by a shift in monocyte differentiation, changing from M2 polarized immunosuppressive macrophages into iNOS+ dendritic cells instead. This differentiation is dependent on an ICB-induced increase in CD40L+ CD8+ T-cells in the tumor immune microenvironment. Our results indicate a novel mechanism in which a ketogenic diet can be used to increase therapeutic efficacy of ICB therapy.

2024-02-13 | GSE206561 | GEO

Preclinical model of anti-PDL1 Immune-checkpoint blockade (ICB) resistance in breast cancer associated to low antigen presentation machinery (APM)

Project description:Immune-checkpoint blockade (ICB) immunotherapy has emerged as one of the most effective therapies in oncology by unleashing anti-tumor response. However, despite the improvement in the clinical outcome of TNBC patients, most patients do not respond yet. Thus, to understand the underlying mechanisms of ICB resistance is necessary. With this purpose, we generated a preclinical immunocompetent syngeneic model of anti-PD-L1 ICB resistance. Mouse breast cancer 4TO7 cells were orthotopically implanted by MFP and at 0.5 x 0.5 cm tumor size mice were treated with anti-PD-L1 (10mg/Kg every 3 days). Though tumors initially responded, they eventually developed resistance to anti-PD-L1 treatment. Immunotherapy resistant tumor (IRT) cells and control tumor cells were isolated and validated again for anti-PDL1 resistance in vivo. RNA from isolated resistant tumor cells was obtained using Qiagen RNA extraction kit. Samples were analyzed by bioanalyzer. Poly-A sequencing was selected for library preparation, and samples were sequenced using Illumina Hi-Seq 2500 platform with 1x50 bp settings in the Centre of Genomic Regulation (CRG). Quality raw data was performed with FastQC software. Raw reads were then aligned with the STAR mapper to the Mus musculus genome and raw counts of reads per gene was additionally obtained with STAR. Differentially expression was assessed using DESeq2 version 1.30.1 package from R/Bioconductor. Among all the results, we have seen that those IRT cells have a downregulation of the antigen presentation machinery (APM) and an enrichment of stemness signatures. Overall, the results support the notion that ICB resistance emerge from low APM activity cell populations with associated stem cell-like phenotype.

2022-01-04 | GSE176580 | GEO

Tumor immunological phenotype signature-based high-throughput screening for the discovery of combination immunotherapy compounds

Project description:Immune checkpoint blockade (ICB) therapy intends to only benefit a fraction of cancer patients, and combination immunotherapy with a compound is a promising treatment to overcome this limitation. Here, a tumor immunological phenotype (TIP) gene signature and high throughput sequencing-based high throughput screening (HTS2) were combined to identify combination immunotherapy compounds. We firstly defined a TIP gene signature, which expression pattern distinguishes “cold” tumors from “hot” tumors, and predicts ICB response in cancer patients. Then, after screening thousands of compounds, we identified that aurora kinase inhibitors, including ENMD-2076 and TAK-901, could reprogram the expression pattern of TIP genes from “cold” tumor to “hot” tumor in triple negative breast cancer (TNBC) cells. The treatment of aurora kinase inhibitors on TNBC cells dramatically up-regulates expression of Th1 type chemokine genes CXCL10 and CXCL11, which promotes effective T cells infiltrating into tumor microenvironment and significantly improves anti-PD-1 efficacy in inhibiting the tumor growth of TNBC in preclinical models. Mechanistically, these aurora kinase inhibitors are mainly through inhibiting AURKA-STAT3 signaling pathway to stimulate the expression of CXCL10 and CXCL11. Our study established a high throughput strategy to discover candidate compounds for combination immunotherapy, and suggested the therapeutic potential of combining aurora kinase inhibitors with checkpoint blockade immunotherapy for the treatment of TNBC.

2020-12-31 | GSE160071 | GEO

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