Lipid Metabolism and Cancer Immunotherapy: Immunosuppressive Myeloid Cells at the Crossroad

Cancer progression generates a chronic inflammatory state that dramatically influences hematopoiesis, originating different subsets of immune cells that can exert pro- or anti-tumor roles. Commitment towards one of these opposing phenotypes is driven by inflammatory and metabolic stimuli derived from the tumor-microenvironment (TME). Current immunotherapy protocols are based on the reprogramming of both specific and innate immune responses, in order to boost the intrinsic anti-tumoral activity of both compartments. Growing pre-clinical and clinical evidence highlights the key role of metabolism as a major influence on both immune and clinical responses of cancer patients. Indeed, nutrient competition (i.e., amino acids, glucose, fatty acids) between proliferating cancer cells and immune cells, together with inflammatory mediators, drastically affect the functionality of innate and adaptive immune cells, as well as their functional cross-talk. This review discusses new advances on the complex interplay between cancer-related inflammation, myeloid cell differentiation and lipid metabolism, highlighting the therapeutic potential of metabolic interventions as modulators of anticancer immune responses and catalysts of anticancer immunotherapy.

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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.

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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.

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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.

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Association of Th2 high tumors with aggressive features of breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e12584 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e12584-e12584

Author(s):

Yoshihisa Tokumaru ◽

Lan Le ◽

Masanori Oshi ◽

Eriko Katsuta ◽

Nobuhisa Matsuhashi ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cancer Progression ◽

Immune Cells ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Th2 Cells ◽

Immune Microenvironment ◽

Adaptive Immune Cells ◽

Tumor Immune Microenvironment

e12584 Background: Recent studies have shown that infiltrating T-lymphocytes have been implicated in the promotion of breast cancer progression. Upon activation, these antigen-presenting cells then recruit adaptive immune cells. It has been proposed that polarization of CD4+ effector T-cells towards the immunosuppressive Th2 cells induce cytokine release and T-cell anergy, which lead to polarization of M2 tumor-associated macrophages (TAM’s), providing a protumorigenic microenvironment. We hypothesized that there is a correlation between high levels of Th2 cells and aggressive features of breast cancer and unfavorable tumor immune environment. Methods: Clinicopathological data and overall survival information was obtained on 1069 breast cancer patients from The Cancer Genome Atlas (TCGA) database. We defined Th2 high and low levels with the median cutoff. Results: Analysis of cell composition of the immune cells within tumor immune microenvironment demonstrated that Th2 high tumors did not consistently associated with unfavorable tumor immune microenvironment. Pro-cancer immune cells, such as macrophage M2 cells were increased with Th2 high tumors whereas, regulatory T cells were decreased with Th2 high tumors (p < 0.01 and p < 0.001 respectively). On the contrary, infiltration of anti-cancer cells, such as macrophage M1 was increased whereas CD8 T cells were decreased with Th2 high tumors (p < 0.05 and p < 0.001 respectively). Th2 was not shown to have correlation with IL-4, IL-6, IL-10 and IL-13, all of which has been reported to associate with Th2 cells. Th2 levels were associated with advanced grades. Also, correlation analysis demonstrated that there was a strong correlation between Th2 levels and Ki-67. These results were further validated with gene set enrichment analysis (GSEA). GSEA revealed that in Th2 high tumors enriched the gene sets associated with cell proliferation and cell cycle. Conclusions: High expression of immunosuppressive Th2 cells was associated with highly proliferative features of breast cancer, but not with unfavorable tumor immune microenvironment.

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The Immune Microenvironment of Breast Cancer Progression

Cancers ◽

10.3390/cancers11091375 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1375 ◽

Cited By ~ 19

Author(s):

Tower ◽

Ruppert ◽

Britt

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Immune Cells ◽

Immune Cell ◽

Early Stage ◽

Invasive Disease ◽

Malignant Tumours ◽

Genetic Changes ◽

Adaptive Immune Cells ◽

Response To Chemotherapy

Inflammation is now recognized as a hallmark of cancer. Genetic changes in the cancer cell are accepted as the match that lights the fire, whilst inflammation is seen as the fuel that feeds the fire. Once inside the tumour, the immune cells secrete cytokines that kick-start angiogenesis to ferry in much-needed oxygen and nutrients that encourage the growth of tumours. There is now irrefutable data demonstrating that the immune contexture of breast tumours can influence growth and metastasis. A higher immune cell count in invasive breast cancer predicts prognosis and response to chemotherapy. We are beginning now to define the specific innate and adaptive immune cells present in breast cancer and their role not just in the progression of invasive disease, but also in the development of pre-invasive lesions and their transition to malignant tumours. This review article focusses on the immune cells present in early stage breast cancer and their relationship with the immunoediting process involved in tumour advancement.

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The therapeutic potential of targeting tryptophan catabolism in cancer

British Journal of Cancer ◽

10.1038/s41416-019-0664-6 ◽

2019 ◽

Vol 122 (1) ◽

pp. 30-44 ◽

Cited By ~ 15

Author(s):

Christiane A. Opitz ◽

Luis F. Somarribas Patterson ◽

Soumya R. Mohapatra ◽

Dyah L. Dewi ◽

Ahmed Sadik ◽

...

Keyword(s):

Clinical Trials ◽

Immune Responses ◽

Cancer Progression ◽

Therapeutic Potential ◽

Positive Impact ◽

Background Information ◽

Catabolic Enzymes ◽

Current State ◽

Tryptophan Catabolism ◽

Alternative Approaches

AbstractBased on its effects on both tumour cell intrinsic malignant properties as well as anti-tumour immune responses, tryptophan catabolism has emerged as an important metabolic regulator of cancer progression. Three enzymes, indoleamine-2,3-dioxygenase 1 and 2 (IDO1/2) and tryptophan-2,3-dioxygenase (TDO2), catalyse the first step of the degradation of the essential amino acid tryptophan (Trp) to kynurenine (Kyn). The notion of inhibiting IDO1 using small-molecule inhibitors elicited high hopes of a positive impact in the field of immuno-oncology, by restoring anti-tumour immune responses and synergising with other immunotherapies such as immune checkpoint inhibition. However, clinical trials with IDO1 inhibitors have yielded disappointing results, hence raising many questions. This review will discuss strategies to target Trp-degrading enzymes and possible down-stream consequences of their inhibition. We aim to provide comprehensive background information on Trp catabolic enzymes as targets in immuno-oncology and their current state of development. Details of the clinical trials with IDO1 inhibitors, including patient stratification, possible effects of the inhibitors themselves, effects of pre-treatments and the therapies the inhibitors were combined with, are discussed and mechanisms proposed that might have compensated for IDO1 inhibition. Finally, alternative approaches are suggested to circumvent these problems.

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Functions of Thrombospondin-1 in the Tumor Microenvironment

International Journal of Molecular Sciences ◽

10.3390/ijms22094570 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4570

Author(s):

Sukhbir Kaur ◽

Steven M. Bronson ◽

Dipasmita Pal-Nath ◽

Thomas W. Miller ◽

David R. Soto-Pantoja ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Suppressor ◽

Immune Cells ◽

Cancer Biology ◽

Therapeutic Potential ◽

Angiogenesis Inhibitor ◽

Genotoxic Stress ◽

Extracellular Vesicle ◽

Adaptive Immune Cells ◽

Thrombospondin 1

The identification of thrombospondin-1 as an angiogenesis inhibitor in 1990 prompted interest in its role in cancer biology and potential as a therapeutic target. Decreased thrombospondin-1 mRNA and protein expression are associated with progression in several cancers, while expression by nonmalignant cells in the tumor microenvironment and circulating levels in cancer patients can be elevated. THBS1 is not a tumor suppressor gene, but the regulation of its expression in malignant cells by oncogenes and tumor suppressor genes mediates some of their effects on carcinogenesis, tumor progression, and metastasis. In addition to regulating angiogenesis and perfusion of the tumor vasculature, thrombospondin-1 limits antitumor immunity by CD47-dependent regulation of innate and adaptive immune cells. Conversely, thrombospondin-1 is a component of particles released by immune cells that mediate tumor cell killing. Thrombospondin-1 differentially regulates the sensitivity of malignant and nonmalignant cells to genotoxic stress caused by radiotherapy and chemotherapy. The diverse activities of thrombospondin-1 to regulate autophagy, senescence, stem cell maintenance, extracellular vesicle function, and metabolic responses to ischemic and genotoxic stress are mediated by several cell surface receptors and by regulating the functions of several secreted proteins. This review highlights progress in understanding thrombospondin-1 functions in cancer and the challenges that remain in harnessing its therapeutic potential.

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A Nomogram Integrating Ferroptosis- and Immune-Related Biomarkers for Prediction of Overall Survival in Lung Adenocarcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.706814 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mengyu Chai ◽

Xiuchun Li ◽

Yaxin Zhang ◽

Yemeng Tang ◽

Pingping Shu ◽

...

Keyword(s):

Overall Survival ◽

Immune Responses ◽

Lung Adenocarcinoma ◽

Tumor Immunity ◽

Immune Cells ◽

Cox Regression ◽

Therapeutic Potential ◽

Clinical Staging ◽

Risk Scores ◽

Immune Related Genes

Ferroptosis plays a dual role in cancer, which is known to be affected to antitumor immune responses. However, the association between ferroptosis and antitumor immune responses is uncertain in lung adenocarcinoma (LUAD). In this work, 38 ferroptosis-related genes (FRGs) and 429 immune-related genes (IRGs) were identified as being differentially expressed between tumor and normal samples. Two risk score formulas consisting of seven FRGs and four IRGs, respectively, were developed by Lasso-penalized Cox regression and verified in the GSE13213 dataset. The CIBERSORT algorithm was used to estimate the relative abundance of immune cells in tumors. The correlation between FRGs and immune cells was evaluated using the TIMER database. The results indicated that the development of ferroptosis was synergistic with that of anti-tumor immunity in LUAD. The concordance index and calibration curves showed that the performance of a nomogram that combines clinical staging and risk scores is superior to that of models using a single prognostic factor. In conclusion, ferroptosis might be synergistic with anti-tumor immunity in LUAD. The combined nomogram could reliably predict the probability of overall survival of LUAD patients. These findings may be useful for future investigation of prognostic value and therapeutic potential related to ferroptosis and tumor immunity in LUAD.

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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.

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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.

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