scholarly journals BCG vaccine and COVID-19: implications for infection prophylaxis and cancer immunotherapy

2020 ◽  
Vol 8 (2) ◽  
pp. e001119 ◽  
Author(s):  
Madhuri Koti ◽  
Alvaro Morales ◽  
Charles H Graham ◽  
David Robert Siemens
Keyword(s):  
Immune Checkpoint ◽  
Critical Role ◽  
Immune Checkpoint Blockade ◽  
Lessons Learned ◽  
Checkpoint Blockade ◽  
Childhood Vaccination ◽  
Infection Prevalence ◽  
Type I ◽  
Infection Prophylaxis ◽  
Vaccination Programs

The COVID-19 pandemic has killed over 400 000 people globally. Ecological evidence indicates that countries with national universal BCG vaccination programs for tuberculosis (TB) prevention have a much lower incidence of severe COVID-19 and mortality compared with those that do not have such programs. BCG is a century old vaccine used for TB prevention via infant/childhood vaccination in lowto middle-income countries with high infection prevalence rate and is known to reduce all-cause neonatal mortality. BCG remains the standard immunotherapy treatment for patients with high-risk non-muscle invasive bladder cancer globally for more than 44 years. Several trials are, therefore, investigating BCG as a prophylactic against COVID-19 in healthcare workers and the elderly. In this commentary, we discuss the potential mechanisms that may underlie BCG associated heterologous protection with a focus on tertiary lymphoid structure (TLS) organogenesis. Given the significance of TLSs in mucosal immunity, their association with positive prognosis and response to immune checkpoint blockade with a critical role of Type I interferon (IFN-1) in inducing these, we also discuss potentiating TLS formation as a promising approach to enhance anti-tumor immunity. We propose that lessons learned from BCG immunotherapy success could be applied to not only augment such microbe-based therapeutics but also lead to similar adjunctive IFN-1 activating approaches to improve response to immune checkpoint blockade therapy in cancer.

scholarly journals cGAS is essential for the antitumor effect of immune checkpoint blockade

2017 ◽  
Vol 114 (7) ◽  
pp. 1637-1642 ◽  
Author(s):  
Hua Wang ◽  
Shuiqing Hu ◽  
Xiang Chen ◽  
Heping Shi ◽  
Chuo Chen ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Antitumor Effect ◽  
Adaptor Protein ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Type I Interferons ◽  
Type I ◽  
Antibody Treatment ◽  
Antitumor Effects ◽  
Cross Presentation

cGMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates innate immune responses. cGAS catalyzes the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce type I interferons (IFNs) and other immune modulatory molecules. Here we show that cGAS is indispensable for the antitumor effect of immune checkpoint blockade in mice. Wild-type, but not cGAS-deficient, mice exhibited slower growth of B16 melanomas in response to a PD-L1 antibody treatment. Consistently, intramuscular delivery of cGAMP inhibited melanoma growth and prolonged the survival of the tumor-bearing mice. The combination of cGAMP and PD-L1 antibody exerted stronger antitumor effects than did either treatment alone. cGAMP treatment activated dendritic cells and enhanced cross-presentation of tumor-associated antigens to CD8 T cells. These results indicate that activation of the cGAS pathway is important for intrinsic antitumor immunity and that cGAMP may be used directly for cancer immunotherapy.

scholarly journals PARPi triggers STING-dependent immune response and enhances therapeutic efficacy of immune checkpoint blockade independent of BRCAness

2018 ◽  
Author(s):  
Jianfeng Shen ◽  
Wei Zhao ◽  
Zhenlin Ju ◽  
Lulu Wang ◽  
Yang Peng ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Therapeutic Efficacy ◽  
Parp Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Dna Lesions ◽  
Checkpoint Blockade ◽  
Type I Interferons ◽  
Therapeutic Effects ◽  
Type I ◽  
Dna Double Strand Breaks

AbstractPoly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPis are believed to exert their therapeutic effects mainly through the blockade of single-strand DNA damage repair, which leads to the accumulation of toxic DNA double strand breaks, specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here, we show that PARPis modulate immune reposes, which contribute to their therapeutic effects independent of BRCA1/2 mutations. The mechanism underlying this PARPi-induced reprogramming of anti-tumor microenvironment involves a promoted accumulation of cytosolic DNA fragments due to unresolved DNA lesions. This in turn activates the DNA sensing cGAS-STING pathway and stimulates production of type I interferons. Ultimately, these events promote PARPi-induced antitumor immunity independent of BRCAness, which can be further enhanced by immune checkpoint blockade. Our results may provide a mechanistic rationale for using PARPis as immunomodulatory agents to harness therapeutic efficacy of immune checkpoint blockade.

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 Hiding in the dark: pan-cancer characterization of expression and clinical relevance of CD40 to immune checkpoint blockade therapy

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Chi Yan ◽  
Ann Richmond
Keyword(s):  
Immune Checkpoint ◽  
Tumor Response ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Type I ◽  
List Type ◽  
Cancer Types ◽  
Pan Cancer ◽  
Cancer Bioinformatics

Highlights CD40 expression correlates with the type I anti-tumor response and better survival. Pan-cancer bioinformatics characterization reveals reduced CD40 expression in 11 cancer types, including RASmut melanoma compared to nevi. RAS mutation correlates with reduced CD40 expression in malignant melanoma. CD40 expression is associated with better response to immune checkpoint blockade therapy in melanoma.

Overcoming resistance to immune checkpoint blockade with RNA-loaded nanoparticles.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 117-117
Author(s):  
Elias Joseph Sayour ◽  
Adam Grippin ◽  
Duane Anthony Mitchell
Keyword(s):  
Immune Checkpoint ◽  
Tumor Antigens ◽  
Defense Mechanism ◽  
Immune Escape ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Type I ◽  
Dependent Manner ◽  
Activation Markers ◽  
Cell Immunity

117 Background: While checkpoint blockade has shown promising survival benefits in patients with solid tumors, immune escape through loss of MHCI expression juxtaposed to an immunoregulatory milieu remain significant hurdles. To overcome these limitations, we developed a novel treatment platform, which leverages the use of commercially available and clinically translatable nanoparticles (NPs) that can be combined with tumor-derived RNA to activate systemic immunity and re-program the intratumoral microenvironment from a regulatory into an immune activated locale. Methods: Since local vaccination strategies are mired with poor immunogenicity, we assessed if i.v. delivery of tumor-derived RNA encapsulated in lipophilic NPs could activate peripheral and intratumoral antigen presenting cells (APCs) for induction of therapeutic anti-tumor immunity in pre-clinical murine melanoma models. Results: We identified a clinically translatable NP formulation that when administered intravenously, mediates release of inflammatory cytokines (i.e. CCL2, IFN-alpha) into serum, systemically activates host APCs in reticuloendothelial organs, and induces precipitous upregulation of MHCI and immune activation markers (i.e. CD86) within the tumor microenvironment. Both model-antigen encoding RNA and physiologically-relevant tumor-derived RNA, when encapsulated in NPs, could expand potent anti-tumor T-cell immunity. We demonstrated that RNA-NPs harness the anti-viral defense mechanism against tumor antigens in a type I interferon dependent manner, and can be further engineered to deliver combinatorial therapies by co-encapsulating mRNAs encoding for immunomodulatory molecules (i.e. HCV PAMPs, GM-CSF). In a pre-clinical melanoma model, RNA-NPs mediate anti-tumor efficacy and significantly enhance activity of immune checkpoint mAbs when used in combination. Conclusions: By employing a systemic RNA-NP formulation encoding for both tumor RNAs and immunomodulatory molecules, as an innovative and versatile platform for delivering combinatorial therapeutics via a single treatment modality, this platform can be harnessed to simultaneously target tumor antigens and re-program the intratumoral microenvironment

scholarly journals LBA10 Critical role of eosinophils during response to immune checkpoint blockade in breast cancer and other cancer types

2020 ◽  
Vol 31 ◽  
pp. S1142
Author(s):  
L. Voorwerk ◽  
H. Garner ◽  
O.S. Blomberg ◽  
L. Spagnuolo ◽  
M. Chalabi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Critical Role ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cancer Types

scholarly journals The developing landscape of combinatorial therapies of immune checkpoint blockade with DNA damage repair inhibitors for the treatment of breast and ovarian cancers

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Lingling Zhu ◽  
Jiewei Liu ◽  
Jiang Chen ◽  
Qinghua Zhou
Keyword(s):  
Dna Damage ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Dna Damage Repair ◽  
Treatment Resistance ◽  
Immune Checkpoint Blockade ◽  
Lessons Learned ◽  
Checkpoint Blockade ◽  
Ovarian Cancers ◽  
Damage Repair

AbstractThe use of immune checkpoint blockade (ICB) using antibodies against programmed death receptor (PD)-1, PD ligand (PD-L)-1, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has redefined the therapeutic landscape in solid tumors, including skin, lung, bladder, liver, renal, and breast tumors. However, overall response rates to ICB therapy remain limited in PD-L1-negative patients. Thus, rational and effective combination therapies will be needed to address ICB treatment resistance in these patients, as well as in PD-L1-positive patients who have progressed under ICB treatment. DNA damage repair inhibitors (DDRis) may activate T-cell responses and trigger inflammatory cytokines release and eventually immunogenic cancer cell death by amplifying DNA damage and generating immunogenic neoantigens, especially in DDR-defective tumors. DDRi may also lead to adaptive PD-L1 upregulation, providing a rationale for PD-L1/PD-1 blockade. Thus, based on preclinical evidence of efficacy and no significant overlapping toxicity, some ICB/DDRi combinations have rapidly progressed to clinical testing in breast and ovarian cancers. Here, we summarize the available clinical data on the combination of ICB with DDRi agents for treating breast and ovarian cancers and discuss the mechanisms of action and other lessons learned from translational studies conducted to date. We also review potential biomarkers to select patients most likely to respond to ICB/DDRi combination therapy.

scholarly journals PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Qi Peng ◽  
Xiangyan Qiu ◽  
Zihan Zhang ◽  
Silin Zhang ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Critical Role ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Tumor Control ◽  
Antigen Uptake

Abstract Immune checkpoint blockade therapies have shown clinical promise in a variety of cancers, but how tumor-infiltrating T cells are activated remains unclear. In this study, we explore the functions of PD-L1 on dendritic cells (DCs), which highly express PD-L1. We observe that PD-L1 on DC plays a critical role in limiting T cell responses. Type 1 conventional DCs are essential for PD-L1 blockade and they upregulate PD-L1 upon antigen uptake. Upregulation of PD-L1 on DC is mediated by type II interferon. While DCs are the major antigen presenting cells for cross-presenting tumor antigens to T cells, subsequent PD-L1 upregulation protects them from killing by cytotoxic T lymphocytes, yet dampens the antitumor responses. Blocking PD-L1 in established tumors promotes re-activation of tumor-infiltrating T cells for tumor control. Our study identifies a critical and dynamic role of PD-L1 on DC, which needs to be harnessed for better invigoration of antitumor immune responses.

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