High-dimensional immune-profiling in cancer: implications for immunotherapy

Immunotherapy is a rapidly growing field for cancer treatment. In contrast to conventional cancer therapies, immunotherapeutic strategies focus on reactivating the immune system to mount an antitumor response. Despite the encouraging outcome in clinical trials, a large proportion of patients still do not respond to treatment and many experience different degrees of immune-related adverse events. Furthermore, it is now increasingly appreciated that even many conventional cancer therapies such as radiotherapy could have a positive impact on the host immune system for better clinical response. Hence, there is a need to better understand tumor immunity in order to design immunotherapeutic strategies, especially evidence-based combination therapies, for improved clinical outcomes. With this aim, cancer research turned its attention to profiling the immune contexture of either the tumor microenvironment (TME) or peripheral blood to uncover mechanisms and biomarkers which might aid in precision immunotherapeutics. Conventional technologies used for this purpose were limited by the depth and dimensionality of the data. Advances in newer techniques have, however, greatly improved the breadth and depth, as well as the quantity and quality of data that can be obtained. The result of these advances is a wealth of new information and insights on how the TME could be affected by various immune cell-types, and how this might in turn impact the clinical outcome of cancer patients . We highlight herein some of the high-dimensional technologies currently employed in immune profiling in cancer and summarize the insights and potential benefits they could bring in designing better cancer immunotherapies.

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Of Mice, Dogs, Pigs, and Men: Choosing the Appropriate Model for Immuno-Oncology Research

ILAR Journal ◽

10.1093/ilar/ily014 ◽

2018 ◽

Vol 59 (3) ◽

pp. 247-262 ◽

Cited By ~ 11

Author(s):

Nana H Overgaard ◽

Timothy M Fan ◽

Kyle M Schachtschneider ◽

Daniel R Principe ◽

Lawrence B Schook ◽

...

Keyword(s):

Immune System ◽

Immune Cell ◽

Tumor Formation ◽

Genetically Engineered ◽

Model Systems ◽

High Rate ◽

Host Immune System ◽

Cancer Immunoediting ◽

Oncology Research ◽

Experimental Cancer

Abstract The immune system plays dual roles in response to cancer. The host immune system protects against tumor formation via immunosurveillance; however, recognition of the tumor by immune cells also induces sculpting mechanisms leading to a Darwinian selection of tumor cell variants with reduced immunogenicity. Cancer immunoediting is the concept used to describe the complex interplay between tumor cells and the immune system. This concept, commonly referred to as the three E’s, is encompassed by 3 distinct phases of elimination, equilibrium, and escape. Despite impressive results in the clinic, cancer immunotherapy still has room for improvement as many patients remain unresponsive to therapy. Moreover, many of the preclinical results obtained in the widely used mouse models of cancer are lost in translation to human patients. To improve the success rate of immuno-oncology research and preclinical testing of immune-based anticancer therapies, using alternative animal models more closely related to humans is a promising approach. Here, we describe 2 of the major alternative model systems: canine (spontaneous) and porcine (experimental) cancer models. Although dogs display a high rate of spontaneous tumor formation, an increased number of genetically modified porcine models exist. We suggest that the optimal immuno-oncology model may depend on the stage of cancer immunoediting in question. In particular, the spontaneous canine tumor models provide a unique platform for evaluating therapies aimed at the escape phase of cancer, while genetically engineered swine allow for elucidation of tumor-immune cell interactions especially during the phases of elimination and equilibrium.

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Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.767041 ◽

2021 ◽

Vol 14 ◽

Author(s):

Elise Liu ◽

Léa Karpf ◽

Delphine Bohl

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Immune System ◽

Frontotemporal Dementia ◽

Immune Cells ◽

Immune Cell ◽

Current Knowledge ◽

Cell Types ◽

Induced Pluripotent ◽

Different Cell Types ◽

Lateral Sclerosis

Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.

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Enabling out-of-clinic human immunity studies via single-cell profiling of capillary blood

10.1101/2020.07.25.210468 ◽

2020 ◽

Author(s):

Tatyana Dobreva ◽

David Brown ◽

Jong Hwee Park ◽

Matt Thomson

Keyword(s):

Gene Expression ◽

Immune System ◽

Environmental Factors ◽

Single Cell ◽

Immune Cell ◽

Cell Types ◽

Capillary Blood ◽

Specific Gene ◽

Human Immune ◽

Over Time

AbstractAn individual’s immune system is driven by both genetic and environmental factors that vary over time. To better understand the temporal and inter-individual variability of gene expression within distinct immune cell types, we developed a platform that leverages multiplexed single-cell sequencing and out-of-clinic capillary blood extraction to enable simplified, cost-effective profiling of the human immune system across people and time at single-cell resolution. Using the platform, we detect widespread differences in cell type-specific gene expression between subjects that are stable over multiple days.SummaryIncreasing evidence implicates the immune system in an overwhelming number of diseases, and distinct cell types play specific roles in their pathogenesis.1,2 Studies of peripheral blood have uncovered a wealth of associations between gene expression, environmental factors, disease risk, and therapeutic efficacy.4 For example, in rheumatoid arthritis, multiple mechanistic paths have been found that lead to disease, and gene expression of specific immune cell types can be used as a predictor of therapeutic non-response.12 Furthermore, vaccines, drugs, and chemotherapy have been shown to yield different efficacy based on time of administration, and such findings have been linked to the time-dependence of gene expression in downstream pathways.21,22,23 However, human immune studies of gene expression between individuals and across time remain limited to a few cell types or time points per subject, constraining our understanding of how networks of heterogeneous cells making up each individual’s immune system respond to adverse events and change over time.

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Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling

Physiological Reviews ◽

10.1152/physrev.00024.2015 ◽

2016 ◽

Vol 96 (3) ◽

pp. 805-829 ◽

Cited By ~ 38

Author(s):

Andreas Wicki ◽

Mario Mandalà ◽

Daniela Massi ◽

Daniela Taverna ◽

Huifang Tang ◽

...

Keyword(s):

Drug Resistance ◽

Immune System ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Acquired Resistance ◽

Therapeutic Strategies ◽

Host Immune System ◽

Cancer Therapies ◽

Acquired Drug Resistance ◽

Physiological Signal

Although modern therapeutic strategies have brought significant progress to cancer care in the last 30 years, drug resistance to targeted monotherapies has emerged as a major challenge. Aberrant regulation of multiple physiological signaling pathways indispensable for developmental and metabolic homeostasis, such as hyperactivation of pro-survival signaling axes, loss of suppressive regulations, and impaired functionalities of the immune system, have been extensively investigated aiming to understand the diversity of molecular mechanisms that underlie cancer development and progression. In this review, we intend to discuss the molecular mechanisms of how conventional physiological signal transduction confers to acquired drug resistance in cancer patients. We will particularly focus on protooncogenic receptor kinase inhibition-elicited tumor cell adaptation through two major core downstream signaling cascades, the PI3K/Akt and MAPK pathways. These pathways are crucial for cell growth and differentiation and are frequently hyperactivated during tumorigenesis. In addition, we also emphasize the emerging roles of the deregulated host immune system that may actively promote cancer progression and attenuate immunosurveillance in cancer therapies. Understanding these mechanisms may help to develop more effective therapeutic strategies that are able to keep the tumor in check and even possibly turn cancer into a chronic disease.

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Potential Roles of Fungal Extracellular Vesicles during Infection

mSphere ◽

10.1128/msphere.00099-16 ◽

2016 ◽

Vol 1 (4) ◽

Cited By ~ 54

Author(s):

Luna S. Joffe ◽

Leonardo Nimrichter ◽

Marcio L. Rodrigues ◽

Maurizio Del Poeta

Keyword(s):

Immune System ◽

Extracellular Vesicles ◽

Virulence Factors ◽

Cell Types ◽

Fungal Diseases ◽

Host Immune System ◽

The Past ◽

Invasive Fungal Diseases

ABSTRACT Extracellular vesicles (EVs) are produced by virtually all cell types. Within the past few years, work in this field has revealed more information about fungal EVs. Fungal EVs have been shown to carry proteins, lipids, pigments, polysaccharides, and RNA; these components are known virulence factors, a fact which supports the hypothesis that fungal EVs concentrate pathogenic determinants. Extracellular vesicles (EVs) are produced by virtually all cell types. Within the past few years, work in this field has revealed more information about fungal EVs. Fungal EVs have been shown to carry proteins, lipids, pigments, polysaccharides, and RNA; these components are known virulence factors, a fact which supports the hypothesis that fungal EVs concentrate pathogenic determinants. Additionally, recent studies have demonstrated that fungal EVs stimulate the host immune system. In this review, putative roles of fungal EVs are discussed, including their potential as vaccination tools and their possible contribution to pathogenesis in invasive fungal diseases.

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The Immune System of Mesothelioma Patients: A Window of Opportunity for Novel Immunotherapies

10.5772/intechopen.98617 ◽

2021 ◽

Author(s):

Fabio Nicolini ◽

Massimiliano Mazza

Keyword(s):

Immune System ◽

Immune Cells ◽

Immune Cell ◽

Current Knowledge ◽

Cell Types ◽

Screening Strategies ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures ◽

Review Current

The interplay between the immune system and the pleural mesothelium is crucial both for the development of malignant pleural mesothelioma (MPM) and for the response of MPM patients to therapy. MPM is heavily infiltrated by several immune cell types which affect the progression of the disease. The presence of organized tertiary lymphoid structures (TLSs) witness the attempt to fight the disease in situ by adaptive immunity which is often suppressed by tumor expressed factors. In rare patients physiological, pharmacological or vaccine-induced immune response is efficient, rendering their plasma a valuable resource of anti-tumor immune cells and molecules. Of particular interest are human antibodies targeting antigens at the tumor cell surface. Here we review current knowledge regarding MPM immune infiltration, MPM immunotherapy and the harnessing of this response to identify novel biologics as biomarkers and therapeutics through innovative screening strategies.

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High dimensional immunotyping of the obese tumor microenvironment reveals model specific adaptation

10.1101/2020.10.14.338806 ◽

2020 ◽

Author(s):

Cara E Wogsland ◽

Hilde E Lien ◽

Line Pedersen ◽

Pahul Hanjra ◽

Sturla M Grondal ◽

...

Keyword(s):

Breast Cancer ◽

Immune Cell ◽

Cell Types ◽

High Dimensional ◽

Low Grade ◽

Cancer Model ◽

Mass Cytometry ◽

Batch Correction ◽

Breast Cancer Model ◽

Cancer Types

AbstractObesity is a disease characterized by chronic low-grade systemic inflammation and has been causally linked to the development of 13 cancer types. Several studies have been undertaken to determine if tumors evolving in obese environments adapt differential interactions with immune cells and if this can be connected to disease outcome. Most of these studies have been limited to single cell lines and tumor models and analysis of limited immune cell populations. Given the multicellular complexity of the immune system and its dysregulation in obesity, we applied high-dimensional suspension mass cytometry to investigate how obesity affects tumor immunity. We used a 36-marker immune-focused mass cytometry panel to interrogate the immune landscape of orthotopic syngeneic mouse models of pancreatic and breast cancer. Unanchored batch correction was implemented to enable simultaneous analysis of tumor cohorts to uncover the immunotypes of each cancer model and reveal remarkably model-specific immune regulation. In the E0771 breast cancer model, we demonstrate an important link to obesity with an increase in two T cell suppressive cell types and a decrease in CD8 T-cells.

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Single-cell RNA sequencing reveals micro-evolution of the stickleback immune system

10.1101/2021.12.20.473470 ◽

2021 ◽

Author(s):

Lauren E Fuess ◽

Daniel I Bolnick

Keyword(s):

Immune System ◽

Single Cell ◽

Immune Cells ◽

Gasterosteus Aculeatus ◽

Immune Cell ◽

Expression Profiles ◽

Cell Types ◽

Model Systems ◽

System Structure ◽

Ecological Processes

Pathogenic infection is an important driver of many ecological processes. Furthermore, variability in immune function is an important driver of differential infection outcomes. New evidence would suggest that immune variation extends to broad cellular structure of immune systems. However, variability at such broad levels is traditionally difficult to detect in non-model systems. Here we leverage single cell transcriptomic approaches to document signatures of microevolution of immune system structure in a natural system, the three-spined stickleback (Gasterosteus aculeatus). We sampled nine adult fish from three populations with variability in resistance to a cestode parasite, Schistocephalus solidus, to create the first comprehensive immune cell atlas for G. aculeatus. Eight major immune cell types, corresponding to major vertebrate immune cells, were identified. We were also able to document significant variation in both abundance and expression profiles of the individual immune cell types, among the three populations of fish. This variability may contribute to observed variability in parasite susceptibility. Finally, we demonstrate that identified cell type markers can be used to reinterpret traditional transcriptomic data. Combined our study demonstrates the power of single cell sequencing to not only document evolutionary phenomena (i.e. microevolution of immune cells), but also increase the power of traditional transcriptomic datasets.

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Comprehensive multi-omics single-cell data integration reveals greater heterogeneity in the human immune system

10.1101/2021.07.25.453651 ◽

2021 ◽

Author(s):

Congmin Xu ◽

Junkai Yang ◽

Astrid Kosters ◽

Benjamin R Babcock ◽

Peng Qiu ◽

...

Keyword(s):

Immune System ◽

Single Cell ◽

Immune Cell ◽

Cell Types ◽

Cell Receptor ◽

Surface Proteins ◽

Cell Type ◽

Human Immune System ◽

Receptor Repertoire ◽

Human Immune

Single-cell transcriptomics enables the definition of diverse human immune cell types across multiple tissue and disease contexts. Still, deeper biological understanding requires comprehensive integration of multiple single-cell omics (transcriptomic, proteomic, and cell receptor repertoire). To improve the identification of diverse cell types and the accuracy of cell-type classification in our multi-omics single-cell datasets, we developed SuPERR-seq, a novel analysis workflow to increase the resolution and accuracy of clustering and allow for the discovery and characterization of previously hidden cell subsets. We show that by incorporating information from cell-surface proteins and immunoglobulin transcript counts, we accurately remove cell doublets and prevent widespread cell-type misclassification. This approach uniquely improves the identification of heterogeneous cell types in the human immune system, including a novel subset of antibody-secreting cells in the bone marrow.

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