scholarly journals Synergy between Toxoplasma gondii type I ΔGRA17 immunotherapy and PD-L1 checkpoint inhibition triggers the regression of targeted and distal tumors

2021 ◽  
Vol 9 (11) ◽  
pp. e002970
Author(s):  
Yu-Chao Zhu ◽  
Hany M Elsheikha ◽  
Jian-Hua Wang ◽  
Shuai Fang ◽  
Jun-Jun He ◽  
...  
Keyword(s):  
Immune Response ◽  
Toxoplasma Gondii ◽  
Tumor Growth ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Complete Regression ◽  
Type I

BackgroundIn this study, we hypothesize that the ability of the protozoan Toxoplasma gondii to modulate immune response within the tumor might improve the therapeutic effect of immune checkpoint blockade. We examined the synergetic therapeutic activity of attenuated T. gondii RH ΔGRA17 strain and programmed death ligand-1 (PD-L1) treatment on both targeted and distal tumors in mice.MethodsThe effects of administration of T. gondii RH ΔGRA17 strain on the tumor volume and survival rate of mice bearing flank B16-F10, MC38, or LLC tumors were studied. We characterized the effects of ΔGRA17 on tumor biomarkers’ expression, PD-L1 expression, immune cells infiltrating the tumors, and expression of immune-related genes by using immunohistochemistry, immunofluorescence, flow cytometry, NanoString platform, and real-time quantitative PCR, respectively. The role of immune cells in the efficacy of ΔGRA17 plus PD-L1 blockade therapy was determined via depletion of immune cell subtypes.ResultsTreatment with T. gondii ΔGRA17 tachyzoites and anti-PD-L1 therapy significantly extended the survival of mice and suppressed tumor growth in preclinical mouse models of melanoma, Lewis lung carcinoma, and colon adenocarcinoma. Attenuation of the tumor growth was detected in the injected and distant tumors, which was associated with upregulation of innate and adaptive immune pathways. Complete regression of tumors was underpinned by late interferon-gamma-producing CD8+ cytotoxic T cells.ConclusionThe results from these models indicate that intratumoral injection of ΔGRA17 induced a systemic effect, improved mouse immune response, and sensitized immunologically ‘cold’ tumors and rendered them sensitive to immune checkpoint blockade therapy.

scholarly journals 765 The first-in-class small molecule TREX1 inhibitor CPI-381 demonstrates type I IFN induction and sensitization of tumors to immune checkpoint blockade

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A800-A800
Author(s):  
Costa Salojin ◽  
Anna Gardberg ◽  
Valerie Vivat ◽  
Lei Cui ◽  
Jeffrey Lauer ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Tumor Growth ◽  
Small Molecule ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Type I ◽  
Type I Ifn ◽  
Syngeneic Tumor

BackgroundTREX1 is an exonuclease that functions as a negative regulator of innate immunity. TREX1 controls dsDNA sensing in tumor and immune cells by preventing aberrant dsDNA buildup that triggers STING-mediated Type 1 Interferon (IFN) induction leading to priming of the adaptive immune system. Loss of function mutations in TREX1 and genetic ablation of trex1 in mice lead to induction of IFNbeta-driven autoimmunity. Thus, TREX1 is a promising target to elicit IFN-mediated anti-tumor immunity.MethodsTo characterize TREX1 inhibitors we developed cell-based assays utilizing human HCT116 carcinoma and THP-1 monocytic Dual reporter cell lines to monitor IRF activity. Activation of cGAS was assessed by measuring cGAMP levels in B16F10 melanoma cells. The potency of TREX1 inhibitors in primary human dendritic cells (DC)s was analyzed by measuring IFNbeta induction by exogenous dsDNA. Analysis of tumor growth inhibition following TREX1 inhibitor treatment was conducted in mouse syngeneic tumor models. TREX1 activity was assessed by measuring degradation of a custom dsDNA substrate.ResultsWe report here the development of a small molecule TREX1 inhibitor, CPI-381, with nanomolar cellular potency, which translated into a robust induction of IRF reporter activity. We observed a significant increase in cGAMP production in B16F10 cells transfected with DNA in the presence of CPI-381, suggesting that CPI-381-mediated inhibition of TREX1 leads to the activation of dsDNA sensors, such as cGAS. Treatment of THP-1 cells with CPI-381 induced the expression of several key ISG involved in innate immunity. Moreover, inhibition of TREX1 with CPI-381 phenocopied the effect of TREX1 genetic deletion in primary human DCs by upregulating IFNbeta. To evaluate whether TREX1 negatively regulates IFNbeta production in syngeneic tumor models, we knocked down trex1 in B16F10, MB49, MC38, and CT26 murine cells. Accumulation of cytosolic dsDNA resulted in a substantial increase in IFNbeta secretion by all four TREX1-KO cell lines.In vivo efficacy studies with CPI-381 demonstrated reduced tumor growth in the MC38 syngeneic tumor model either alone or in combination with anti-PD1. We observed a reduction of TREX1 activity in CPI-381 treated tumors, confirming an inverse relationship between TREX1 intra-tumor activity and tumor growth, and efficient target engagement after systemic (oral) delivery.ConclusionsWe have developed a first-in-class, potent TREX1 inhibitor demonstrating excellent in vitro and in vivo potency via enhancement of cytosolic dsDNA sensing and induction of IFNbeta in cancer and immune cells. CPI-381-induced tumor-intrinsic TREX1 inhibition elicits antitumor immunity as a single agent and increases response to immune checkpoint blockade via mechanisms downstream of TREX1 that activate type I IFN signaling.Ethics ApprovalAll animal work was approved and conducted under the oversight of the Charles River Accelerator and Development Lab (CRADL, Cambridge, MA) Institutional Animal Care and Use Committee (protocol # 2021-1258).

scholarly journals A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. Farias ◽  
A. Soto ◽  
F. Puttur ◽  
C. J. Goldin ◽  
S. Sosa ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Therapeutic Effect ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Combined Treatment ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Regulatory Cells ◽  
Ifn Γ

AbstractBrucella lumazine synthase (BLS) is a homodecameric protein that activates dendritic cells via toll like receptor 4, inducing the secretion of pro-inflammatory cytokines and chemokines. We have previously shown that BLS has a therapeutic effect in B16 melanoma-bearing mice only when administered at early stages of tumor growth. In this work, we study the mechanisms underlying the therapeutic effect of BLS, by analyzing the tumor microenvironment. Administration of BLS at early stages of tumor growth induces high levels of serum IFN-γ, as well as an increment of hematopoietic immune cells within the tumor. Moreover, BLS-treatment increases the ratio of effector to regulatory cells. However, all treated mice eventually succumb to the tumors. Therefore, we combined BLS administration with anti-PD-1 treatment. Combined treatment increases the outcome of both monotherapies. In conclusion, we show that the absence of the therapeutic effect at late stages of tumor growth correlates with low levels of serum IFN-γ and lower infiltration of immune cells in the tumor, both of which are essential to delay tumor growth. Furthermore, the combined treatment of BLS and PD-1 blockade shows that BLS could be exploited as an essential immunomodulator in combination therapy with an immune checkpoint blockade to treat skin cancer.

scholarly journals Lenalidomide Enhances Immune Checkpoint Blockade-Induced Immune Response in Multiple Myeloma

2015 ◽  
Vol 21 (20) ◽  
pp. 4607-4618 ◽  
Author(s):  
Güllü Görgün ◽  
Mehmet K. Samur ◽  
Kristen B. Cowens ◽  
Steven Paula ◽  
Giada Bianchi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune Response ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5912
Author(s):  
Angèle Luby ◽  
Marie-Clotilde Alves-Guerra
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Metabolic Stress ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Therapeutic Approaches ◽  
Immunosuppressive Tumor Microenvironment

Over the past decade, advances in cancer immunotherapy through PD1–PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.

scholarly journals Combination of epigenetic regulation with gene therapy-mediated immune checkpoint blockade induces anti-tumour effects and immune response in vivo

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huapan Fang ◽  
Zhaopei Guo ◽  
Jie Chen ◽  
Lin Lin ◽  
Yingying Hu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Response ◽  
Epigenetic Regulation ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Memory ◽  
Escape Mechanism ◽  
Immune Escape Mechanism

AbstractImmunotherapy has become a powerful cancer treatment, but only a small fraction of patients have achieved durable benefits due to the immune escape mechanism. In this study, epigenetic regulation is combined with gene therapy-mediated immune checkpoint blockade to relieve this immune escape mechanism. PPD (i.e., mPEG-b-PLG/PEI-RT3/DNA) is developed to mediate plasmid-encoding shPD-L1 delivery by introducing multiple interactions (i.e., electrostatic, hydrogen bonding, and hydrophobic interactions) and polyproline II (PPII)-helix conformation, which downregulates PD-L1 expression on tumour cells to relieve the immunosuppression of T cells. Zebularine (abbreviated as Zeb), a DNA methyltransferase inhibitor (DNMTi), is used for the epigenetic regulation of the tumour immune microenvironment, thus inducing DC maturation and MHC I molecule expression to enhance antigen presentation. PPD plus Zeb combination therapy initiates a systemic anti-tumour immune response and effectively prevents tumour relapse and metastasis by generating durable immune memory. This strategy provides a scheme for tumour treatment and the inhibition of relapse and metastasis.

scholarly journals The Crosstalk Between Malignant Cells and Tumor-Promoting Immune Cells Relevant to Immunotherapy in Pancreatic Ductal Adenocarcinoma

2022 ◽  
Vol 9 ◽  
Author(s):  
Xuefei Liu ◽  
Ziwei Luo ◽  
Xuechen Ren ◽  
Zhihang Chen ◽  
Xiaoqiong Bao ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Rna Sequencing ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Ductal Adenocarcinoma ◽  
Malignant Cells ◽  
Sequencing Data ◽  
Immunosuppressive Microenvironment

Background: Pancreatic ductal adenocarcinoma (PDAC) is dominated by an immunosuppressive microenvironment, which makes immune checkpoint blockade (ICB) often non-responsive. Understanding the mechanisms by which PDAC forms an immunosuppressive microenvironment is important for the development of new effective immunotherapy strategies.Methods: This study comprehensively evaluated the cell-cell communications between malignant cells and immune cells by integrative analyses of single-cell RNA sequencing data and bulk RNA sequencing data of PDAC. A Malignant-Immune cell crosstalk (MIT) score was constructed to predict survival and therapy response in PDAC patients. Immunological characteristics, enriched pathways, and mutations were evaluated in high- and low MIT groups.Results: We found that PDAC had high level of immune cell infiltrations, mainly were tumor-promoting immune cells. Frequent communication between malignant cells and tumor-promoting immune cells were observed. 15 ligand-receptor pairs between malignant cells and tumor-promoting immune cells were identified. We selected genes highly expressed on malignant cells to construct a Malignant-Immune Crosstalk (MIT) score. MIT score was positively correlated with tumor-promoting immune infiltrations. PDAC patients with high MIT score usually had a worse response to immune checkpoint blockade (ICB) immunotherapy.Conclusion: The ligand-receptor pairs identified in this study may provide potential targets for the development of new immunotherapy strategy. MIT score was established to measure tumor-promoting immunocyte infiltration. It can serve as a prognostic indicator for long-term survival of PDAC, and a predictor to ICB immunotherapy response.

scholarly journals Integrative Tumor and Immune Cell Multi-omic Analyses Predict Response to Immune Checkpoint Blockade in Melanoma

2020 ◽  
Vol 1 (8) ◽  
pp. 100139
Author(s):  
Valsamo Anagnostou ◽  
Daniel C. Bruhm ◽  
Noushin Niknafs ◽  
James R. White ◽  
Xiaoshan M. Shao ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Biomarkers for Response to Immune Checkpoint Blockade

2020 ◽  
Vol 4 (1) ◽  
pp. 331-351
Author(s):  
Shridar Ganesan ◽  
Janice Mehnert
Keyword(s):  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Clinical Activity ◽  
Host Immune System ◽  
Mutation Burden ◽  
Life Threatening ◽  
Expression Evaluation ◽  
Distinct Features

Immune checkpoint blockade (ICB) has significant clinical activity in diverse cancer classes and can induce durable remissions in even refractory advanced disease. However, only a minority of cancer patients treated with ICB have long-term benefits, and ICB treatment is associated with significant, potentially life-threatening, autoimmune side effects. There is a great need to develop biomarkers of response to guide patient selection to maximize the chance of benefit and prevent unnecessary toxicity, and current biomarkers do not have optimal positive or negative predictive value. A variety of potential biomarkers are currently being developed, including those based on assessment of checkpoint protein expression, evaluation of tumor-intrinsic features including mutation burden and viral infection, evaluation of features of the tumor immune microenvironment including nature of immune cell infiltration, and features of the host such as composition of the gut microbiome. Better understanding of the underlying fundamental mechanisms of immune response and resistance to ICB, along with the use of complementary assays that interrogate distinct features of the tumor, the tumor microenvironment, and host immune system, will allow more precise use of these therapies to optimize patient outcomes.

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