Role of the intestinal microbiome and microbial-derived metabolites in immune checkpoint blockade immunotherapy of cancer

AbstractImmune checkpoint inhibitors (ICIs) are monoclonal antibodies that block immune inhibitory pathways. Administration of ICIs augments T cell-mediated immune responses against tumor, resulting in improved overall survival in cancer patients. It has emerged that the intestinal microbiome can modulate responses to ICIs via the host immune system and that the use of antibiotics can lead to reduced efficacy of ICIs. Recently, reports that fecal microbiota transplantation can lead to ICI therapy responses in patients previously refractory to therapy suggest that targeting the microbiome may be a viable strategy to reprogram the tumor microenvironment and augment ICI therapy. Intestinal microbial metabolites may also be linked to response rates to ICIs. In addition to response rates, certain toxicities that can arise during ICI therapy have also been found to be associated with the intestinal microbiome, including in particular colitis. A key mechanistic question is how certain microbes can enhance anti-tumor responses or, alternatively, predispose to ICI-associated colitis. Evidence has emerged that the intestinal microbiome can modulate outcomes to ICI therapies via two major mechanisms, including those that are antigen-specific and those that are antigen-independent. Antigen-specific mechanisms occur when epitopes are shared between microbial and tumor antigens that could enhance, or, alternatively, reduce anti-tumor immune responses via cross-reactive adaptive immune cells. Antigen-independent mechanisms include modulation of responses to ICIs by engaging innate and/or adaptive immune cells. To establish microbiome-based biomarkers of outcomes and specifically modulate the intestinal microbiome to enhance efficacy of ICIs in cancer immunotherapy, further prospective interventional studies will be required.

Download Full-text

P01.10 IFNy secretion of adaptive and innate immune cells as a parameter to display leukaemia derived dendritic cell (DCleu) mediated immune responses in AML

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-itoc7.23 ◽

2020 ◽

Vol 8 (Suppl 2) ◽

pp. A13.1-A13

Author(s):

LK Klauer ◽

O Schutti ◽

S Ugur ◽

F Doraneh-Gard ◽

N Rogers ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Immune Cells ◽

Gm Csf ◽

Adaptive Immune ◽

Cik Cells ◽

Adaptive Immune Cells ◽

Suitable Parameter

BackgroundMyeloid leukaemic blasts can be converted into leukaemia derived dendritic cells (DCleu) with blastmodulatory Kit-I and Kit-M, which have the competence to regularly activate T and immunoreactive cells to gain anti-leukaemic activity or rather cytotoxicity. As innate and adaptive immune responses are notably promoted by the cytokine interferon gamma (IFNy), we hypothesised that the IFNy secretion could be a suitable parameter to display DC/DCleu mediated immunologic activity and even anti-leukaemic cytotoxicity.Materials and MethodsDC/DCleu were generated from leukaemic WB with Kit-I (GM-CSF + OK-432) and Kit-M (GM-CSF + PGE1) and used to stimulate T cell enriched immunoreactive cells. Initiated anti-leukaemic cytotoxicity was investigated with a cytotoxicity fluorolysis assay (CTX). Initiated IFNy secretion of innate and adaptive immune cells (T cells, TCD4+ cells, TCD8+ cells, NKCD56+ cells, NKCD161+ cells, CIKCD56+ cells, CIKCD161+ cells and iNKT) was investigated with a cytokine secretion assay (CSA). In some cases IFNy production was additionally evaluated with an intracellular cytokine assay (ICA). Conclusively, the IFNy secretion of immunoreactive cells was correlated with the anti-leukaemic cytotoxicity.ResultsSignificant amounts of DC and DCleu as well as migratory DC and DCleu could be generated with Kit-I and Kit-M without induction of blast proliferation. T cell enriched immunoreactive cells stimulated with DC/DCleu showed an increased anti-leukaemic cytotoxicity and an increased IFNy secretion of T, NK and CIK cells compared to control. Both the CSA and ICA yielded comparable amounts of IFNy positive innate and adaptive immune cells. The correlation between the IFNy secretion of immunoreactive cells and the anti-leukaemic cytotoxicity showed a positive relationship in T cells, TCD4+ cells, TCD8+ cells and NKCD56+ cells.ConclusionsWe found blastmodulatory Kit-I and Kit-M competent to generate DC/DCleu from leukaemic WB. Stimulation of T cell enriched immunoreactive cells with DC/DCleu regularly resulted in an increased anti-leukaemic cytotoxicity and an increased IFNy dependent immunological activity of T, NK and CIK cells compared to control. Moreover the anti-leukaemic cytotoxicity positively correlated with the IFNy secretion in T cells, TCD4+ cells, TCD8+ cells, NKCD56+ cells. We therefore consider the IFNy secretion of innate and adaptive immune cells to be a suitable parameter to assess the efficacy of in vitro and potentially in vivo AML immunotherapy. The CSA in this regard proved to be a convenient and reproducible technique to detect and phenotypically characterise IFNy secreting cells of the innate and adaptive immune system.Disclosure InformationL.K. Klauer: None. O. Schutti: None. S. Ugur: None. F. Doraneh-Gard: None. N. Rogers: None. M. Weinmann: None. D. Krämer: None. A. Rank: None. C. Schmid: None. B. Eiz-Vesper: None. H.M. Schmetzer: None.

Download Full-text

Lactate-Dependent Regulation of Immune Responses by Dendritic Cells and Macrophages

Frontiers in Immunology ◽

10.3389/fimmu.2021.691134 ◽

2021 ◽

Vol 12 ◽

Author(s):

Indumathi Manoharan ◽

Puttur D. Prasad ◽

Muthusamy Thangaraju ◽

Santhakumar Manicassamy

Keyword(s):

Dendritic Cells ◽

Immune Responses ◽

Immune Cells ◽

Adaptive Immune Responses ◽

Effector Functions ◽

Tissue Microenvironment ◽

Adaptive Immune ◽

Pathological Conditions ◽

Recent Advances ◽

Adaptive Immune Cells

For decades, lactate has been considered an innocuous bystander metabolite of cellular metabolism. However, emerging studies show that lactate acts as a complex immunomodulatory molecule that controls innate and adaptive immune cells’ effector functions. Thus, recent advances point to lactate as an essential and novel signaling molecule that shapes innate and adaptive immune responses in the intestine and systemic sites. Here, we review these recent advances in the context of the pleiotropic effects of lactate in regulating diverse functions of immune cells in the tissue microenvironment and under pathological conditions.

Download Full-text

The Role of the Inflammatory Response in Mediating Functional Recovery Following Composite Tissue Injuries

International Journal of Molecular Sciences ◽

10.3390/ijms222413552 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13552

Author(s):

Naveena B. Janakiram ◽

Michael S. Valerio ◽

Stephen M. Goldman ◽

Christopher L. Dearth

Keyword(s):

Wound Healing ◽

Immune Responses ◽

Immune Cells ◽

Military Service ◽

Adaptive Immune Responses ◽

Impaired Wound Healing ◽

Composite Tissue ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Tissue Injuries

Composite tissue injuries (CTI) are common among US Military Service members during combat operations, and carry a high potential of morbidity. Furthermore, CTI are often complicated due to an altered wound healing response, resulting in part from a dysregulation of the innate and adaptive immune responses. Unlike normal wound healing, in CTI, disruptions occur in innate immune responses, altering neutrophil functions, macrophage activation and polarization, further impacting the functions of T regulatory cells. Additionally, the biological underpinnings of these unfavorable wound healing conditions are multifactorial, including various processes, such as: ischemia, hypoxia, low nutrient levels, and altered cell metabolic pathways, among others, all of which are thought to trigger anergy in immune cells and destabilize adaptive immune responses. As a result, impaired wound healing is common in CTI. Herein, we review the altered innate and adaptive immune cells and their metabolic status and responses following CTI, and discuss the role a multi-pronged immunomodulatory approach may play in facilitating improved outcomes for afflicted patients.

Download Full-text

Discrete immune response signature to SARS-CoV-2 mRNA vaccination versus infection

10.1101/2021.04.20.21255677 ◽

2021 ◽

Author(s):

Ellie N. Ivanova ◽

Joseph C. Devlin ◽

Terkild B. Buus ◽

Akiko Koide ◽

Amber Cornelius ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Immune Cells ◽

Transcriptional Profiling ◽

Cell Receptor ◽

Interferon Response ◽

Effector Cells ◽

Adaptive Immune ◽

Adaptive Immune Cells

AbstractBoth SARS-CoV-2 infection and vaccination elicit potent immune responses. A number of studies have described immune responses to SARS-CoV-2 infection. However, beyond antibody production, immune responses to COVID-19 vaccines remain largely uncharacterized. Here, we performed multimodal single-cell sequencing on peripheral blood of patients with acute COVID-19 and healthy volunteers before and after receiving the SARS-CoV-2 BNT162b2 mRNA vaccine to compare the immune responses elicited by the virus and by this vaccine. Phenotypic and transcriptional profiling of immune cells, coupled with reconstruction of the B and T cell antigen receptor rearrangement of individual lymphocytes, enabled us to characterize and compare the host responses to the virus and to defined viral antigens. While both infection and vaccination induced robust innate and adaptive immune responses, our analysis revealed significant qualitative differences between the two types of immune challenges. In COVID-19 patients, immune responses were characterized by a highly augmented interferon response which was largely absent in vaccine recipients. Increased interferon signaling likely contributed to the observed dramatic upregulation of cytotoxic genes in the peripheral T cells and innate-like lymphocytes in patients but not in immunized subjects. Analysis of B and T cell receptor repertoires revealed that while the majority of clonal B and T cells in COVID-19 patients were effector cells, in vaccine recipients clonally expanded cells were primarily circulating memory cells. Importantly, the divergence in immune subsets engaged, the transcriptional differences in key immune populations, and the differences in maturation of adaptive immune cells revealed by our analysis have far-ranging implications for immunity to this novel pathogen.

Download Full-text

A comprehensive logic-based model of the human immune system to study the dynamics responses to mono- and coinfections

10.1101/2020.03.11.988238 ◽

2020 ◽

Author(s):

Bhanwar Lal Puniya ◽

Robert Moore ◽

Akram Mohammed ◽

Rada Amin ◽

Alyssa La Fleur ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

Immune Responses ◽

Immune Cells ◽

Computational Models ◽

Single Infection ◽

Human Immune System ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Human Immune

AbstractThe human immune system, which protects against pathogens and diseases, is a complex network of cells and molecules. The effects of complex dynamical interactions of pathogens and immune cells on the immune response can be studied using computational models. However, a model of the entire immune system is still lacking. Here, we developed a comprehensive computational model that integrates innate and adaptive immune cells, cytokines, immunoglobulins, and nine common pathogens from different classes of virus, bacteria, parasites, and fungi. This model was used to investigate the dynamics of the immune system under two scenarios: (1) single infection with pathogens, and (2) various medically relevant pathogen coinfections. In coinfections, we found that the order of infecting pathogens has a significant impact on the dynamics of cytokines and immunoglobulins. Thus, our model provides a tool to simulate immune responses under different dosage of pathogens and their combinations, which can be further extended and used as a tool for drug discovery and immunotherapy. Furthermore, the model provides a comprehensive and simulatable blueprint of the human immune system as a result of the synthesis of the vast knowledge about the network-like interactions of various components of the system.

Download Full-text

Mesenchymal Stem Cells, Immune Cells and Tumor Cells Crosstalk: A Sinister Triangle in the Tumor Microenvironment

Current Stem Cell Research & Therapy ◽

10.2174/1574888x13666180816114809 ◽

2019 ◽

Vol 14 (1) ◽

pp. 43-51 ◽

Cited By ~ 3

Author(s):

Mahboobeh Razmkhah ◽

Shabnam Abtahi ◽

Abbas Ghaderi

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Microenvironment ◽

Immune Responses ◽

Tumor Cells ◽

Immune Cells ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Adaptive Immune ◽

Adaptive Immune Cells

Mesenchymal Stem Cells [MSCs] are a heterogeneous population of fibroblast-like cells which maintain self-renewability and pluripotency. Many studies have demonstrated the immunomodulatory effects of MSCs on the innate and adaptive immune cells. As a result of interactions with tumor cells, microenvironment and immune-stimulating milieu, MSCs contribute to tumor progression by several mechanisms, including sustained proliferative signal in cancer stem cells [CSCs], inhibition of tumor cell apoptosis, transition to tumor-associated fibroblasts [TAFs], promotion of angiogenesis, stimulation of epithelial-mesenchymal transition [EMT], suppression of immune responses, and consequential promotion of tumor metastasis. Here, we present an overview of the latest findings on Janusfaced roles that MSCs play in the tumor microenvironment [TME], with a concise focus on innate and adaptive immune responses.

Download Full-text

miRNA as a Modulator of Immunotherapy and Immune Response in Melanoma

Biomolecules ◽

10.3390/biom11111648 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1648

Author(s):

Mai-Huong Thi Nguyen ◽

Yueh-Hsia Luo ◽

An-Lun Li ◽

Jen-Chieh Tsai ◽

Kun-Lin Wu ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Cancer Progression ◽

Immune Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Clinical Applicability ◽

Melanoma Patients

Immune checkpoint inhibitors are a promising therapy for the treatment of cancers, including melanoma, that improved benefit clinical outcomes. However, a subset of melanoma patients do not respond or acquire resistance to immunotherapy, which limits their clinical applicability. Recent studies have explored the reasons related to the resistance of melanoma to immune checkpoint inhibitors. Of note, miRNAs are the regulators of not only cancer progression but also of the response between cancer cells and immune cells. Investigation of miRNA functions within the tumor microenvironment have suggested that miRNAs could be considered as key partners in immunotherapy. Here, we reviewed the known mechanism by which melanoma induces resistance to immunotherapy and the role of miRNAs in immune responses and the microenvironment.

Download Full-text

Sargramostim and immune checkpoint inhibitors: combinatorial therapeutic studies in metastatic melanoma

Immunotherapy ◽

10.2217/imt-2021-0119 ◽

2021 ◽

Author(s):

Ahmad A Tarhini ◽

Ila Joshi ◽

Fiona Garner

Keyword(s):

Immune Responses ◽

Metastatic Melanoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Unmet Needs ◽

Checkpoint Inhibitors ◽

Advanced Melanoma ◽

Clinical Activity ◽

Gm Csf ◽

Adaptive Immune

The use of immune checkpoint inhibitors in patients with metastatic melanoma generates clinical benefit, including improved survival. Yet disease resistance and immune-related adverse events persist as unmet needs. Sargramostim, a yeast-derived recombinant human GM-CSF, has shown clinical activity against diverse solid tumors, including metastatic melanoma. Here we review the use of sargramostim for treatment of advanced melanoma. Potential sargramostim applications in melanoma draw on the unique ability of GM-CSF to link innate and adaptive immune responses. We review preclinical and translational data describing the mechanism of action of sargramostim and synergy with immune checkpoint inhibitors to enhance efficacy and reduce treatment-related toxicity.

Download Full-text

Current status of cancer immunotherapy with immune checkpoint inhibitors

Journal of Korean Medical Association ◽

10.5124/jkma.2021.64.5.326 ◽

2021 ◽

Vol 64 (5) ◽

pp. 326-331

Author(s):

Myung Ah Lee

Keyword(s):

Tumor Microenvironment ◽

Immune Responses ◽

Tumor Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Therapeutic Agents ◽

Chemotherapeutic Agents ◽

Current Status ◽

Host Immune System

The clinical outcome in advanced cancer has improved since the development of targeted therapies and immune checkpoint inhibitors. We can expect better overall survival after a combination treatment with these therapeutic agents. Classical cytotoxic chemotherapeutic agents directly kill tumor cells by destroying the cell structure and DNA of tumor cells or inhibiting their metabolism. Targeted therapy also directly affects tumor cells by inhibiting the cell growth signaling system. Conversely, immune checkpoint inhibitors can enhance immune responses by using the host immune system in the tumor microenvironment, leading to the direct killing of tumor cells. Therefore, immune checkpoint inhibitors are less toxic and have longer response durations. Even in solid tumors with nonimmunogenic backgrounds, cytotoxic chemotherapy or targeted treatment can induce immune responses to place the tumor microenvironment in an immunogenic state. Synergistic anticancer effects can be expected when immune checkpoint inhibitors are added during this state. Moreover, drug resistance may be overcome by combination therapies. If patients with cancer are treated with a combination of these therapeutic agents and the characteristics of each tumor are identified with data from next generation sequencing, personalized treatments can be tailored, making it possible to control cancers as a curable disease just like other benign chronic diseases.

Download Full-text