Innate Immunity and Cancer Pathophysiology

Chronic inflammation increases the risk of several cancers, including gastric, colon, and hepatic cancers. Conversely, tumors, similar to tissue injury, trigger an inflammatory response coordinated by the innate immune system. Cellular and molecular mediators of inflammation modulate tumor growth directly and by influencing the adaptive immune response. Depending on the balance of immune cell types and signals within the tumor microenvironment, inflammation can support or restrain the tumor. Adding to the complexity, research from the past two decades has revealed that innate immune cells are highly heterogeneous and plastic, with variable phenotypes depending on tumor type, stage, and treatment. The field is now on the cusp of being able to harness this wealth of data to ( a) classify tumors on the basis of their immune makeup, with implications for prognosis, treatment choice, and clinical outcome, and ( b) design therapeutic strategies that activate antitumor immune responses by targeting innate immune cells. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Immunology and cytokine pathways

10.1093/med/9780198737582.003.0007 ◽

2018 ◽

Author(s):

Bruce Kirkham

Keyword(s):

Psoriatic Arthritis ◽

Immune Cells ◽

Cell Function ◽

Immune Cell ◽

Adaptive Immune Response ◽

Innate Immune ◽

Innate Immune Cells ◽

New Information ◽

Key Pathways

Psoriatic arthritis immunopathology has become the subject of intense study. These findings show differences to other forms of inflammatory arthritis in key pathways. Increased knowledge of innate immunity and the important role of IL-17/23 biology in both psoriasis and psoriatic arthritis, have led to new theories of immunopathogenesis in both conditions. Direct environmental stimuli could trigger innate immune cells resident in skin, which may then initiate a chronic adaptive immune response. The joint has fewer resident innate immune cells, but new studies show cells producing IL-17 may play key roles in immunopathology. The new information summarized here will provide important hypotheses for investigation of pathogenic pathways. Differences in non-immune cell function may also be critical mediators of response, for example, production of IL-12 or IL-23 by dendritic cells. Keratinocytes in skin and fibroblasts in joints may be critical in mediating cytokine production and effector function.

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Microglia and Central Nervous System–Associated Macrophages—From Origin to Disease Modulation

Annual Review of Immunology ◽

10.1146/annurev-immunol-093019-110159 ◽

2021 ◽

Vol 39 (1) ◽

Author(s):

Marco Prinz ◽

Takahiro Masuda ◽

Michael A. Wheeler ◽

Francisco J. Quintana

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Immune Cells ◽

Cell Biology ◽

Treatment Options ◽

Myeloid Cell ◽

Innate Immune ◽

Annual Review ◽

Publication Date ◽

Innate Immune Cells

The immune system of the central nervous system (CNS) consists primarily of innate immune cells. These are highly specialized macrophages found either in the parenchyma, called microglia, or at the CNS interfaces, such as leptomeningeal, perivascular, and choroid plexus macrophages. While they were primarily thought of as phagocytes, their function extends well beyond simple removal of cell debris during development and diseases. Brain-resident innate immune cells were found to be plastic, long-lived, and host to an outstanding number of risk genes for multiple pathologies. As a result, they are now considered the most suitable targets for modulating CNS diseases. Additionally, recent single-cell technologies enhanced our molecular understanding of their origins, fates, interactomes, and functional cell states during health and perturbation. Here, we review the current state of our understanding and challenges of the myeloid cell biology in the CNS and treatment options for related diseases. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Innate Immune Cells and Their Contribution to T-Cell-Based Immunotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms21124441 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4441 ◽

Cited By ~ 1

Author(s):

Pierpaolo Ginefra ◽

Girieca Lorusso ◽

Nicola Vannini

Keyword(s):

T Cells ◽

T Cell ◽

Cancer Immunotherapy ◽

Cancer Patients ◽

Immune Cells ◽

Adoptive Cell Therapy ◽

Adaptive Immune Response ◽

Immune Checkpoint Blockade ◽

Innate Immune ◽

Innate Immune Cells

In recent years, immunotherapy has become the most promising therapy for a variety of cancer types. The development of immune checkpoint blockade (ICB) therapies, the adoptive transfer of tumor-specific T cells (adoptive cell therapy (ACT)) or the generation of T cells engineered with chimeric antigen receptors (CAR) have been successfully applied to elicit durable immunological responses in cancer patients. However, not all the patients respond to these therapies, leaving a consistent gap of therapeutic improvement that still needs to be filled. The innate immune components of the tumor microenvironment play a pivotal role in the activation and modulation of the adaptive immune response against the tumor. Indeed, several efforts are made to develop strategies aimed to harness innate immune cells in the context of cancer immunotherapy. In this review, we describe the contribution of innate immune cells in T-cell-based cancer immunotherapy and the therapeutic approaches implemented to broaden the efficacy of these therapies in cancer patients.

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Evidence for B cell maturation but not trained immunity in uninfected infants exposed to hepatitis C virus

Gut ◽

10.1136/gutjnl-2019-320269 ◽

2020 ◽

Vol 69 (12) ◽

pp. 2203-2213 ◽

Cited By ~ 1

Author(s):

Anton Lutckii ◽

Benedikt Strunz ◽

Anton Zhirkov ◽

Olga Filipovich ◽

Elena Rukoiatkina ◽

...

Keyword(s):

Immune System ◽

B Cells ◽

B Cell ◽

Immune Cells ◽

Immune Cell ◽

Innate Immune ◽

Cell Maturation ◽

Innate Immune Cells ◽

B Cell Maturation ◽

Exposed Uninfected

ObjectivesVertical transmission of hepatitis C virus (HCV) is rare compared with other chronic viral infections, despite that newborns have an immature, and possibly more susceptible, immune system. It further remains unclear to what extent prenatal and perinatal exposure to HCV affects immune system development in neonates.DesignTo address this, we studied B cells, innate immune cells and soluble factors in a cohort of 62 children that were either unexposed, exposed uninfected or infected with HCV. Forty of these infants were followed longitudinally from birth up until 18 months of age.ResultsAs expected, evidence for B cell maturation was observed with increased age in children, whereas few age-related changes were noticed among innate immune cells. HCV-infected children had a high frequency of HCV-specific IgG-secreting B cells. Such a response was also detected in some exposed but uninfected children but not in uninfected controls. Consistent with this, both HCV-exposed uninfected and HCV-infected infants had evidence of early B cell immune maturation with an increased proportion of IgA-positive plasma cells and upregulated CD40 expression. In contrast, actual HCV viraemia, but not mere exposure, led to alterations within myeloid immune cell populations, natural killer (NK) cells and a distinct soluble factor profile with increased levels of inflammatory cytokines and chemokines.ConclusionOur data reveal that exposure to, and infection with, HCV causes disparate effects on adaptive B cells and innate immune cell such as myeloid cells and NK cells in infants.

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Engineering advanced logic and distributed computing in human CAR immune cells

Nature Communications ◽

10.1038/s41467-021-21078-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jang Hwan Cho ◽

Atsushi Okuma ◽

Katri Sofjan ◽

Seunghee Lee ◽

James J. Collins ◽

...

Keyword(s):

Immune Cells ◽

Communication Channel ◽

Immune Cell ◽

Cell Types ◽

Innate Immune ◽

Innate Immune Cells ◽

Complex Phenotypes ◽

Car T ◽

Different Cell Types ◽

Multiple Immune Cell

AbstractThe immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels. The ability to reprogram such an interconnected multicellular system holds enormous promise in treating various diseases, as exemplified by the use of chimeric antigen receptor (CAR) T cells as cancer therapy. However, most CAR designs lack computation features and cannot reprogram multiple immune cell types in a coordinated manner. Here, leveraging our split, universal, and programmable (SUPRA) CAR system, we develop an inhibitory feature, achieving a three-input logic, and demonstrate that this programmable system is functional in diverse adaptive and innate immune cells. We also create an inducible multi-cellular NIMPLY circuit, kill switch, and a synthetic intercellular communication channel. Our work highlights that a simple split CAR design can generate diverse and complex phenotypes and provide a foundation for engineering an immune cell consortium with user-defined functionalities.

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Lipopolysaccharide modulates neutrophil recruitment and macrophage polarization on lymphatic vessels and impairs lymphatic function in rat mesentery

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00467.2015 ◽

2015 ◽

Vol 309 (12) ◽

pp. H2042-H2057 ◽

Cited By ~ 25

Author(s):

Sanjukta Chakraborty ◽

Scott D. Zawieja ◽

Wei Wang ◽

Yang Lee ◽

Yuan J. Wang ◽

...

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Contractile Activity ◽

Macrophage Polarization ◽

Lymphatic Vessels ◽

Innate Immune ◽

Innate Immune Cells ◽

Lymphatic Function ◽

Inflammatory Conditions ◽

Rat Mesentery

Impairment of the lymphatic system is apparent in multiple inflammatory pathologies connected to elevated endotoxins such as LPS. However, the direct mechanisms by which LPS influences the lymphatic contractility are not well understood. We hypothesized that a dynamic modulation of innate immune cell populations in mesentery under inflammatory conditions perturbs tissue cytokine/chemokine homeostasis and subsequently influences lymphatic function. We used rats that were intraperitoneally injected with LPS (10 mg/kg) to determine the changes in the profiles of innate immune cells in the mesentery and in the stretch-mediated contractile responses of isolated lymphatic preparations. Results demonstrated a reduction in the phasic contractile activity of mesenteric lymphatic vessels from LPS-injected rats and a severe impairment of lymphatic pump function and flow. There was a significant reduction in the number of neutrophils and an increase in monocytes/macrophages present on the lymphatic vessels and in the clear mesentery of the LPS group. This population of monocytes and macrophages established a robust M2 phenotype, with the majority showing high expression of CD163 and CD206. Several cytokines and chemoattractants for neutrophils and macrophages were significantly changed in the mesentery of LPS-injected rats. Treatment of lymphatic muscle cells (LMCs) with LPS showed significant changes in the expression of adhesion molecules, VCAM1, ICAM1, CXCR2, and galectin-9. LPS-TLR4-mediated regulation of pAKT, pERK pI-κB, and pMLC20 in LMCs promoted both contractile and inflammatory pathways. Thus, our data provide the first evidence connecting the dynamic changes in innate immune cells on or near the lymphatics and complex cytokine milieu during inflammation with lymphatic dysfunction.

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Elucidating the Innate Immunological Effects of Mild Magnetic Hyperthermia on U87 Human Glioblastoma Cells: An in vitro Study

10.20944/preprints202108.0494.v1 ◽

2021 ◽

Author(s):

Stefano Persano ◽

Francesco Vicini ◽

Alessandro Poggi ◽

Jordi Leonardo Castrillo Fernandez ◽

Giusy Maria Rita Rizzo ◽

...

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Nk Cell ◽

Magnetic Hyperthermia ◽

Innate Immune ◽

Target Cells ◽

Innate Immune Cells ◽

Glioblastoma Cells ◽

Mild Hyperthermia ◽

Wide Range

Cancer immunotherapies are gaining a large popularity and many of them have been approved as standard second-line or in some cases even as first-line treatment for a wide range of cancers. However, immunotherapy has not shown a clinically relevant success in glioblastoma (GBM), principally due to the brain’s “immune-privileged” status and the peculiar tumor microenvironment (TME) of GBM featured by lack of presence of tumor-infiltrating lymphocytes and the establishment of immunosuppressive mechanisms. Emerging evidence has highlighted the key role played by innate immune cells in immunosurveillance and in initiating and driving immune responses against GBM. Immunogenic cell death (ICD) is a promising approach to elicit direct activation of the innate immune system by inducing in target cancer cells the expression of molecular signatures recognized through a repertoire of innate immune cell pattern recognition receptors (PRRs) by effector innate immune cells. Herein, we explored local mild thermal treatment, generated by using ultrasmall (size ~ 17 nm) cubic-shaped iron oxide nanoparticles exposed to an external alternating magnetic field (AMF), to induce ICD in U87 glioblastoma cells. In accordance with what has been previously observed with other types of tumors, we found that mild hyperthermia modulates the immunological profile of U87 glioblastoma cells by inducing stress-associated signals leading to enhanced phagocytosis and killing of U87 cells by macrophages. Finally, we demonstrated that mild magnetic hyperthermia has a modulatory effect on the expression of inhibitory and activating NK cell ligands on target cells. Interestingly, alteration in the expression of NK ligands, caused by mild hyperthermia treatment, in U87 glioblastoma cells, increased their susceptibility to NK cell killing and NK cell functionality. The overall findings demonstrate that mild magnetic hyperthermia stimulates ICD and sensitizes GBM cells to NK-mediated killing by inducing the upregulation of specific stress ligands, providing a novel immunotherapeutic approach for GBM treatment, with potential to synergize with existing NK cell-based therapies thus improving their therapeutic outcomes.

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Dietary and Physiological Effects of Zinc on the Immune System

Annual Review of Nutrition ◽

10.1146/annurev-nutr-122019-120635 ◽

2021 ◽

Vol 41 (1) ◽

Author(s):

Inga Wessels ◽

Henrike Josephine Fischer ◽

Lothar Rink

Keyword(s):

Immune Responses ◽

Immune Cells ◽

Immune Cell ◽

Current Knowledge ◽

Annual Review ◽

Publication Date ◽

Biological Processes ◽

And Function ◽

Broad Overview

Evidence for the importance of zinc for all immune cells and for mounting an efficient and balanced immune response to various environmental stressors has been accumulating in recent years. This article describes the role of zinc in fundamental biological processes and summarizes our current knowledge of zinc's effect on hematopoiesis, including differentiation into immune cell subtypes. In addition, the important role of zinc during activation and function of immune cells is detailed and associated with the specific immune responses to bacteria, parasites, and viruses. The association of zinc with autoimmune reactions and cancers as diseases with increased or decreased immune responses is also discussed. This article provides a broad overview of the manifold roles that zinc, or its deficiency, plays in physiology and during various diseases. Consequently, we discuss why zinc supplementation should be considered, especially for people at risk of deficiency. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1710754114 ◽

2017 ◽

Vol 114 (39) ◽

pp. 10455-10460 ◽

Cited By ~ 38

Author(s):

Keehoon Jung ◽

Takahiro Heishi ◽

Joao Incio ◽

Yuhui Huang ◽

Elizabeth Y. Beech ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Growth ◽

Immune Cells ◽

Immune Cell ◽

Antiangiogenic Therapy ◽

Innate Immune ◽

Growth Delay ◽

Innate Immune Cells ◽

Tumor Growth Delay ◽

Anti Vegf

Antiangiogenic therapy with antibodies against VEGF (bevacizumab) or VEGFR2 (ramucirumab) has been proven efficacious in colorectal cancer (CRC) patients. However, the improvement in overall survival is modest and only in combination with chemotherapy. Thus, there is an urgent need to identify potential underlying mechanisms of resistance specific to antiangiogenic therapy and develop strategies to overcome them. Here we found that anti-VEGFR2 therapy up-regulates both C-X-C chemokine ligand 12 (CXCL12) and C-X-C chemokine receptor 4 (CXCR4) in orthotopic murine CRC models, including SL4 and CT26. Blockade of CXCR4 signaling significantly enhanced treatment efficacy of anti-VEGFR2 treatment in both CRC models. CXCR4 was predominantly expressed in immunosuppressive innate immune cells, which are recruited to CRCs upon anti-VEGFR2 treatment. Blockade of CXCR4 abrogated the recruitment of these innate immune cells. Importantly, these myeloid cells were mostly Ly6Clow monocytes and not Ly6Chigh monocytes. To selectively deplete individual innate immune cell populations, we targeted key pathways in Ly6Clow monocytes (Cx3cr1−/− mice), Ly6Chigh monocytes (CCR2−/− mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 blockade in SL4 CRCs. Depletion of Ly6Clow monocytes or neutrophils improved anti-VEGFR2–induced SL4 tumor growth delay similar to the CXCR4 blockade. In CT26 CRCs, highly resistant to anti-VEGFR2 therapy, CXCR4 blockade enhanced anti-VEGFR2–induced tumor growth delay but specific depletion of Ly6G+ neutrophils did not. The discovery of CXCR4-dependent recruitment of Ly6Clow monocytes in tumors unveiled a heretofore unknown mechanism of resistance to anti-VEGF therapies. Our findings also provide a rapidly translatable strategy to enhance the outcome of anti-VEGF cancer therapies.

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Monocytes and macrophages in tissue repair: Implications for immunoregenerative biomaterial design

Experimental Biology and Medicine ◽

10.1177/1535370216650293 ◽

2016 ◽

Vol 241 (10) ◽

pp. 1084-1097 ◽

Cited By ~ 154

Author(s):

Molly E Ogle ◽

Claire E Segar ◽

Sraeyes Sridhar ◽

Edward A Botchwey

Keyword(s):

Inflammatory Response ◽

Immune Cells ◽

Tissue Repair ◽

Tissue Injury ◽

Critical Role ◽

Myeloid Cells ◽

Innate Immune ◽

Innate Immune Cells ◽

Signaling Systems ◽

Monocytes And Macrophages

Monocytes and macrophages play a critical role in tissue development, homeostasis, and injury repair. These innate immune cells participate in guiding vascular remodeling, stimulation of local stem and progenitor cells, and structural repair of tissues such as muscle and bone. Therefore, there is a great interest in harnessing this powerful endogenous cell source for therapeutic regeneration through immunoregenerative biomaterial engineering. These materials seek to harness specific subpopulations of monocytes/macrophages to promote repair by influencing their recruitment, positioning, differentiation, and function within a damaged tissue. Monocyte and macrophage phenotypes span a continuum of inflammatory (M1) to anti-inflammatory or pro-regenerative cells (M2), and their heterogeneous functions are highly dependent on microenvironmental cues within the injury niche. Increasing evidence suggests that division of labor among subpopulations of monocytes and macrophages could allow for harnessing regenerative functions over inflammatory functions of myeloid cells; however, the complex balance between necessary functions of inflammatory versus regenerative myeloid cells remains to be fully elucidated. Historically, biomaterial-based therapies for promoting tissue regeneration were designed to minimize the host inflammatory response; although, recent appreciation for the roles that innate immune cells play in tissue repair and material integration has shifted this paradigm. A number of opportunities exist to exploit known signaling systems of specific populations of monocytes/macrophages to promote repair and to better understand the biological and pathological roles of myeloid cells. This review seeks to outline the characteristics of distinct populations of monocytes and macrophages, identify the role of these cells within diverse tissue injury niches, and offer design criteria for immunoregenerative biomaterials given the intrinsic inflammatory response to their implantation.

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