scholarly journals Immune System Alterations in Multiple Myeloma: Molecular Mechanisms and Therapeutic Strategies to Reverse Immunosuppression

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1353
Author(s):  
Andrea Díaz-Tejedor ◽  
Mauro Lorenzo-Mohamed ◽  
Noemí Puig ◽  
Ramón García-Sanz ◽  
María-Victoria Mateos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Cytotoxic Effects ◽  
Disease Evolution ◽  
Immune Effector ◽  
Effector Cells ◽  
Surface Molecules ◽  
Immune Effector Cells

Immunosuppression is a common feature of multiple myeloma (MM) patients and has been associated with disease evolution from its precursor stages. MM cells promote immunosuppressive effects due to both the secretion of soluble factors, which inhibit the function of immune effector cells, and the recruitment of immunosuppressive populations. Alterations in the expression of surface molecules are also responsible for immunosuppression. In this scenario, immunotherapy, as is the case of immunotherapeutic monoclonal antibodies (mAbs), aims to boost the immune system against tumor cells. In fact, mAbs exert part of their cytotoxic effects through different cellular and soluble immune components and, therefore, patients’ immunosuppressive status could reduce their efficacy. Here, we will expose the alterations observed in symptomatic MM, as compared to its precursor stages and healthy subjects, in the main immune populations, especially the inhibition of effector cells and the activation of immunosuppressive populations. Additionally, we will revise the mechanisms responsible for all these alterations, including the interplay between MM cells and immune cells and the interactions among immune cells themselves. We will also summarize the main mechanisms of action of the four mAbs approved so far for the treatment of MM. Finally, we will discuss the potential immune-stimulating effects of non-immunotherapeutic drugs, which could enhance the efficacy of immunotherapeutic treatments.

scholarly journals Transcriptomic Correlates of Immunologic Activation in Head and Neck and Cervical Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Cristina Saiz-Ladera ◽  
Mariona Baliu-Piqué ◽  
Francisco J. Cimas ◽  
Aránzazu Manzano ◽  
Vanesa García-Barberán ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Immune System ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Immune Effector ◽  
Effector Cells ◽  
Favorable Prognosis ◽  
Immune Effector Cells ◽  
Tumor Types

Targeting the immune system has emerged as an effective therapeutic strategy for the treatment of various tumor types, including Head and Neck Squamous Cell Carcinoma (HNSCC) and Non-small-Cell Lung Cancer (NSCLC), and checkpoint inhibitors have shown to improve patient survival in these tumor types. Unfortunately, not all cancers respond to these agents, making it necessary to identify responsive tumors. Several biomarkers of response have been described and clinically tested. As of yet what seems to be clear is that a pre-activation state of the immune system is necessary for these agents to be efficient. In this study, using established transcriptomic signatures, we identified a group of gene combination associated with favorable outcome in HNSCC linked to a higher presence of immune effector cells. CD2, CD3D, CD3E, and CXCR6 combined gene expression is associated with improved outcome of HNSCC patients and an increase of infiltrating immune effector cells. This new signature also identifies a subset of cervical squamous cell carcinoma (CSCC) patients with favorable prognosis, who show an increased presence of immune effector cells in the tumor, which outcome shows similarities with the HP-positive HNSCC cohort of patients. In addition, CD2, CD3D, CD3E, and CXCR6 signature is able to predict the best favorable prognosis in terms of overall survival of CSSC patients. Of note, these findings were not reproduced in other squamous cell carcinomas like esophageal SCC or lung SCC. Prospective confirmatory studies should be employed to validate these findings.

scholarly journals The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3542
Author(s):  
Joanna Domagala ◽  
Mieszko Lachota ◽  
Marta Klopotowska ◽  
Agnieszka Graczyk-Jarzynka ◽  
Antoni Domagala ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Nk Cell ◽  
Metabolic Changes ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Almost All

NK cells have unique capabilities of recognition and destruction of tumor cells, without the requirement for prior immunization of the host. Maintaining tolerance to healthy cells makes them an attractive therapeutic tool for almost all types of cancer. Unfortunately, metabolic changes associated with malignant transformation and tumor progression lead to immunosuppression within the tumor microenvironment, which in turn limits the efficacy of various immunotherapies. In this review, we provide a brief description of the metabolic changes characteristic for the tumor microenvironment. Both tumor and tumor-associated cells produce and secrete factors that directly or indirectly prevent NK cell cytotoxicity. Here, we depict the molecular mechanisms responsible for the inhibition of immune effector cells by metabolic factors. Finally, we summarize the strategies to enhance NK cell function for the treatment of tumors.

scholarly journals Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

2021 ◽  
Vol 12 ◽  
Author(s):  
Yijia Li ◽  
Yangzhe Wu ◽  
Yi Hu
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Immune Cells ◽  
Expression Patterns ◽  
Immune Effector ◽  
Effector Cells ◽  
Cell Functions ◽  
Metabolic Plasticity ◽  
Signal Transduction Networks ◽  
Immune Effector Cells

Cellular metabolism of both cancer and immune cells in the acidic, hypoxic, and nutrient-depleted tumor microenvironment (TME) has attracted increasing attention in recent years. Accumulating evidence has shown that cancer cells in TME could outcompete immune cells for nutrients and at the same time, producing inhibitory products that suppress immune effector cell functions. Recent progress revealed that metabolites in the TME could dysregulate gene expression patterns in the differentiation, proliferation, and activation of immune effector cells by interfering with the epigenetic programs and signal transduction networks. Nevertheless, encouraging studies indicated that metabolic plasticity and heterogeneity between cancer and immune effector cells could provide us the opportunity to discover and target the metabolic vulnerabilities of cancer cells while potentiating the anti-tumor functions of immune effector cells. In this review, we will discuss the metabolic impacts on the immune effector cells in TME and explore the therapeutic opportunities for metabolically enhanced immunotherapy.

scholarly journals 671 Biological impacts of standard of care chemotherapies on immune effector cells from AML patients

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A699-A699
Author(s):  
Dmitry Zhigarev ◽  
Alexander MacFarlane ◽  
Christina Drenberg ◽  
Reza Nejati ◽  
Asya Varshavsky ◽  
...  
Keyword(s):  
Nk Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Phenotype ◽  
Second Line ◽  
Color Flow ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
And Function

BackgroundAcute myeloid leukemia (AML) is a heterogeneous group of malignant bone marrow diseases, characterized by massive and uncontrolled proliferation of myeloid precursor cells, which alters normal blood cell ratios. This disease is common to older adults and collectively displays one of the lowest 5-year overall survival rates (<25%) among all cancers, currently representing the deadliest form of leukemia. Improved treatments are clearly needed, and immunotherapies are attractive candidate therapies to explore.There are currently several standard chemotherapeutic treatment schemes for AML, which could be divided into two major groups: (1) cytotoxic chemotherapy (“7+3” or daunorubicin-cytarabine) and (2) hypomethylating agents (HMAs). HMAs include both 5-azacytidine and decitabine, which are cytidine analogs that inhibit DNA methyltransferase, resulting in the hypomethylation of DNA and inducing expression of silenced gene loci. Currently, HMAs are routinely delivered in combination with the Bcl-2 inhibitor venetoclax.The goals of this study are to determine how these standard first line therapies can affect the frequency and functional integrity of effector immune cells in patients' blood and establish when the phenotype and function of immune cells are restored to identify time windows when second line immunotherapies could be most effective.MethodsMore than 100 blood samples were obtained from 33 previously untreated AML patients. More than 50 measurable biomarkers were analyzed using 14-color flow cytometry to assess immune phenotypes of T and NK cells in peripheral blood of AML patients prior to treatment and at up to four timepoints after initiation of treatment with HMA or chemotherapy.ResultsWe found several significant changes in immune cell phenotype and function that occur in response to these therapies. Treatment with HMAs was strikingly less impactful on immune cells in patients compared to previously published in vitro studies. Nevertheless, HMA treatment increased perforin levels in T and NK cells, inhibited IFN-gamma secretion by CD8+ T cells, and changed expression of several checkpoint molecules. While chemotherapy caused fewer phenotypic changes it dramatically decreased the total number of immune cells. We also determined viable, functional and phenotypical recovery periods for immune effector cells after the treatments.ConclusionsOur results are important for introducing new second line immunotherapies to these chemotherapeutic regimens for treating AML and to improve overall understanding of immune cell behavior under conditions of anti-tumor treatment.AcknowledgementsSupported by grants from Janssen and the U.S./Israel Binational Science Foundation.Ethics ApprovalThe study was approved by the Fox Chase Cancer Center Institutional Review Board, approval number 17-8010, and all patients provided informed consent before taking part in the study.

scholarly journals The right microbial stimulus can direct innate immune effector cells to specific organ sites to clear pathology

2019 ◽  
Author(s):  
Shirin Kalyan ◽  
Mark Bazett ◽  
Ho Pan Sham ◽  
Momir Bosiljcic ◽  
Beryl Luk ◽  
...  
Keyword(s):  
Immune System ◽  
Innate Immune ◽  
Immune Memory ◽  
Immune Effector ◽  
Effector Cells ◽  
Adaptive Immune ◽  
Immune Effector Cells ◽  
Innate Immune Effector ◽  
Organ Site ◽  
Tissue Site

ABSTRACTRecent developments in understanding how the functional phenotype of the innate immune system is programmed has led to paradigm-shifting views on immunomodulation. These advances have overturned two long-held dogmas: only adaptive immunity confers immunological memory and innate immunity lacks specificity. This work describes the novel observation that innate immune effector cells can be recruited to specific tissues of the body where pathology is present by using a microbial-based immune stimulus that consists of an inactivated pathogen that typically resides or causes infection in that target tissue site. We demonstrate this principle using experimental models of cancer and infection for which different subcutaneously delivered microbial-based treatments were shown to induce the recruitment of immune effector cells to specific diseased organs. Amelioration of disease in a given organ niche was dependent on matching the correct microbial stimulus for the affected organ site but was independent of the nature of the pathology. This observation intriguingly suggests that the immune system, upon pathogen recognition, tends to direct its resources to the compartment in which the pathogen has previously been encountered and would be the most likely source of infection. Importantly, this phenomenon provides a novel means to therapeutically target innate immune effector cells to sites of specific disease localization to potentially treat a wide spectrum of pathologies, including cancer, infection, and chronic inflammatory disorders.AUTHOR SUMMARYVaccines that target adaptive immune memory have revolutionized medicine. This study describes a novel strategy that works as a modified innate immune “vaccine” that exploits the trained response of innate immune effector cells to clear pathology in a specific tissue site. Unlike memory of the adaptive immune system, which functions like a lock and key, innate immune memory is more akin to a reflex response – like experienced muscle or neural cells that are changed by a stimulus to respond more efficiently upon re-exposure. This change in behavior through experience is the definition of learning. Our study suggests that this innate immune learning occurs at different levels. Emergency hematopoiesis trains new innate immune cells in the bone marrow to respond quickly and effectively to a non-specific threat; whereas, pathogen-specific training occurs at sites where cells making up the immunologic niche have had interactions with a particular pathogen and have been trained to respond more robustly to it upon re-presentation in the context of a danger signal. The speed with which new immune cells are trained in the bone marrow in response to an imminent microbial threat and their subsequent recruitment to the target organ site where that microbe typically resides suggests there are ways the immune system communicates to coordinate this rapid response that are yet to be fully delineated. These findings provide a novel highly proficient way to harness the potent effector functions of the innate immune system to address a wide range of immune-based diseases.

scholarly journals Microglia in Health and Disease: The Strength to Be Diverse and Reactive

2021 ◽  
Vol 15 ◽  
Author(s):  
Oihane Uriarte Huarte ◽  
Lorraine Richart ◽  
Michel Mittelbronn ◽  
Alessandro Michelucci
Keyword(s):  
Molecular Mechanisms ◽  
Brain Regions ◽  
Brain Diseases ◽  
Dependent Manner ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
The Central Nervous System ◽  
Health And Disease ◽  
Reactive Properties

Microglia are the resident immune effector cells of the central nervous system (CNS) rapidly reacting to any perturbation in order to maintain CNS homeostasis. Although their outstanding reactive properties have been elucidated over the last decades, their heterogeneity in healthy tissue, such as across brain regions, as well as their diversity in the development and progression of brain diseases, are currently opening new avenues to understand the cellular and functional states of microglia subsets in a context-dependent manner. Here, we review the main breakthrough studies that helped in elucidating microglia heterogeneity in the healthy and diseased brain and might pave the way to critical functional screenings of the inferred cellular diversity. We suggest that unraveling the cellular and molecular mechanisms underlying specific functionalities of microglial subpopulations, which may ultimately support or harm the neuronal network in neurodegenerative diseases, or may acquire pro- or anti-tumorigenic phenotypes in brain tumors, will possibly uncover new therapeutic avenues for to date non-curable neurological disorders.

scholarly journals Antiinflammatory and Immunomodulating Properties of Fungal Metabolites

2005 ◽  
Vol 2005 (2) ◽  
pp. 63-80 ◽  
Author(s):  
Cristina Lull ◽  
Harry J. Wichers ◽  
Huub F. J. Savelkoul
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Effects ◽  
Fungal Metabolites ◽  
Necrosis Factor Alpha ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Factor Alpha ◽  
Active Substances ◽  
Necrosis Factor

We discuss current information on the ability of extracts and isolated metabolites from mushrooms to modulate immune responses. This can result in a more enhanced innate and acquired disease resistance. The major immunomodulating effects of these active substances derived from mushrooms include mitogenicity and activation of immune effector cells, such as lymphocytes, macrophages, and natural killer cells, resulting in the production of cytokines, including interleukins (ILs), tumor necrosis factor alpha (TNF)-α, and interferon gamma (INF)-γ. In particular, the ability of selective mushroom extracts to modulate the differentiation capacity of CD4+T cells to mature into TH1and/or TH2subsets will be discussed. As a consequence these extracts will have profound effects in particular diseases, like chronic autoimmune TH1-mediated or allergic TH2-mediated diseases. Immunosuppressive effects by mushroom components have also been observed. The therapeutic effects of mushrooms, such as anticancer activity, suppression of autoimmune diseases, and allergy have been associated with their immunomodulating effects. However, further studies are needed to determine the molecular mechanisms of the immunomodulating effects of mushrooms metabolites both individually and in complex mixtures, for example, extracts.

scholarly journals A Novel Class of Bifunctional Immunotherapeutic That Exploit a Universal Antibody Binding Terminus (uABT) to Recruit Endogenous Antibodies to Cells Expressing CD38 Demonstrates Anti-Multiple Myeloma Activity in Vitro and Ex Vivo against Patient Tumor Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4411-4411
Author(s):  
Ann Marie Rossi ◽  
Anna Bunin ◽  
Lawrence Iben ◽  
Matthew Welsch ◽  
Tanya Berbasova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Ex Vivo ◽  
Employment Equity ◽  
Myeloma Cells ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Human Igg1 ◽  
Equity Ownership

Background: Antibody recruiting molecules (ARM) are novel, immunotherapeutic bifunctional molecules composed of two active termini connected by a linker. One of the termini binds to a target molecule on a cancer cell. The other terminus, called universal antibody binding terminus (uABT), recruit all endogenous IgG antibodies independent of their antigen binding specificity. As a result, the target cell is "opsonized" by antibodies which then bring the immune effector cells to eliminate the target through various antibody-dependent destruction mechanisms. Kleo Pharmaceuticals has developed a series of CD38-ARM mlecules which target human CD38 highly expressed by multiple myeloma cells. CD38-ARM compounds are able to mediate ADCC without depleting CD38 expressing immune effector cells like existing therapeutic antibodies such as Daratumumab. Methods: Cyclized peptides containing natural and non-natural amino-acid that selectively bind to human CD38 were identified using Peptidream Flexizyme-based, cell free Peptide Discovery Translation System. These peptides were linked to uABT antibody binder via a linker to generate the final CD38-ARM molecules Binding of CD38-ARM was tested by ternary complex formation between CD38 expressing cells, CD38-ARM and labelled human IgG1. To confirm the activity of CD38-ARM, surrogate CD16a binding and signaling assays were performed using the NFAT Promega system. Antibody dependent cellular cytotoxicity (ADCC) assays using purified NK cells from multiple donors with polymorphism variants (V/V, F/F, and V/F) of CD16a were performed to confirm activity. Live cell imaging was utilized to assess the dynamics of NK-RAJI cell interactions mediated by CD38-ARM +/- IgG. We evaluated the ability of compounds to mediate complement dependent cytotoxicity (CDC). We tested the effect of CD38-ARM on human immune cell populations within PBMC and whole bone marrow (WBM) by flow cytometry. Lastly, ex vivo samples from WBM of MM patients at diagnosis or relapse were used to evaluate CD38-ARM anti-tumor activity as well as off-target effects, without the addition of external source of IgG, through multiparametric flow-cytometry (CD45, CD19, CD38, CD138, CD56, CD27, CD8, CD117). Results: The CD38-ARM were shown to have the ability to bind to CD38 with a 7nM affinity and to human IgG1 and IgG2 with affinity of 15nM and 11nM by SPR. Activity of KP compounds was observed in all assays except for CDC. In ternary assay, KP-6 had an apparent EC50 of 16nM while KP-7's EC50 was 6nM. Both KP-6 and 7 had comparable EC50s in the single digit nanamolar range in the NFAT activation assay induced by CD16a binding was confirmed using human IgG to induce, while Daratumumab had an apparent EC50 of 0.04nM. In the ADCC assay, both KP-6 & KP-7 had EC50s of 7 & 6nM respectively, while Daratumumab had an EC50 of 0.1nM. In addition, no NK cell depletion was observed when PBMC were treated with KP compounds, whereas a profound reduction in both percentages and absolute numbers in this cell subset was observed with Daratumumab treatment. Increasing dose of CD38-ARM (range 0.1uM- 25uM) were tested in ex vivo WBM samples from MM patients together with a negative control and Daratumumab. At concentrations of 10uM and 25uM, CD38-ARM induced a significant reduction of MM cells achieving results comparable to those of Daratumumab activity (p >0.05 in both cases), while sparing all other CD38+ normal cells such as NK, T lymphocytes, monocytes and granulocytes, which are always reduced in the presence of Daratumumab. Conclusions: CD38-ARMs are able to kill MM cells by ADCC without depleting CD38 expressing immune cells contrary to existing antibodies such as Daratumumab. CD38-ARMs do not activate complement, which might be involved in the infusion reaction seen with Daratumumab. Most importantly, CD38-ARMs kill multiple myeloma cells ex vivo in patient bone marrow samples as well as plasma cell leukemia in patient blood. Combined with the in vivo efficacy data presented elsewhere, this data establishes the therapeutic potential of CD38-ARM. They also represent the first demonstration of the ARM platform ability to generate therapeutic agents tailored to a specific indication, by varying target binding moiety of the molecule. Disclosures Rossi: Kleo pharmaceuticals: Employment, Equity Ownership. Bunin:Kleo pharmaceuticals: Employment, Equity Ownership. Iben:Kleo Pharmaceuticals: Employment, Equity Ownership. Welsch:Kleo pharmaceuticals: Employment, Equity Ownership. Berbasova:Kleo Pharmaceuticals: Employment, Equity Ownership. Riillo:Kleo Pharmaceuticals: Research Funding. Ohuchi:Peptidream Inc.: Employment. Alvarez:Kleo pharmaceuticals: Employment, Equity Ownership. Kawakami:Peptidream Inc.: Employment. Nagasawa:Peptidream Inc.: Employment. Spiegel:Kleo pharmaceuticals: Equity Ownership. Rastelli:Kleo pharmaceuticals: Employment, Equity Ownership.

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