scholarly journals Metabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints

2021 ◽  
Vol 11 ◽  
Author(s):  
Yaolin Xu ◽  
Lijie He ◽  
Qiang Fu ◽  
Junzhe Hu
Keyword(s):  
Clinical Trials ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Mitochondrial Biogenesis ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Tumor Therapy ◽  
Nucleotide Metabolism ◽  
Metabolic Reprogramming ◽  
Immune Checkpoints

Immune checkpoint inhibitors (ICIs), Ipilimumab, Nivolumab, Pembrolizumab and Atezolizumab, have been applied in anti-tumor therapy and demonstrated exciting performance compared to conventional treatments. However, the unsatisfactory response rates, high recurrence and adaptive resistance limit their benefits. Metabolic reprogramming appears to be one of the crucial barriers to immunotherapy. The deprivation of required nutrients and altered metabolites not only promote tumor progression but also confer dysfunction on immune cells in the tumor microenvironment (TME). Glycolysis plays a central role in metabolic reprogramming and immunoregulation in the TME, and many therapies targeting glycolysis have been developed, and their combinations with ICIs are in preclinical and clinical trials. Additional attention has been paid to the role of amino acids, lipids, nucleotides and mitochondrial biogenesis in metabolic reprogramming and clinical anti-tumor therapy. This review attempts to describe reprogramming metabolisms within tumor cells and immune cells, from the aspects of glycolysis, amino acid metabolism, lipid metabolism, nucleotide metabolism and mitochondrial biogenesis and their impact on immunity in the TME, as well as the significance of targeting metabolism in anti-tumor therapy, especially in combination with ICIs. In particular, we highlight the expression mechanism of programmed cell death (ligand) 1 [PD-(L)1] in tumor cells and immune cells under reprogramming metabolism, and discuss in detail the potential of targeting key metabolic pathways to break resistance and improve the efficacy of ICIs based on results from current preclinical and clinical trials. Besides, we draw out biomarkers of potential predictive value in ICIs treatment from a metabolic perspective.

scholarly journals Targeted Tumor Therapy Remixed—An Update on the Use of Small-Molecule Drugs in Combination Therapies

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 155 ◽  
Author(s):  
Martina Gatzka
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Small Molecule ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Therapy ◽  
Metabolic Reprogramming ◽  
Comprehensive Overview ◽  
Small Molecule Drugs ◽  
Mutational Status

Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted.

scholarly journals Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Michaël Cerezo ◽  
Stéphane Rocchi
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Metabolic Pathways ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Metabolic Reprogramming ◽  
Limited Resources ◽  
Antitumor Response ◽  
Secondary Resistance

Abstract By targeting the tumor microenvironment to stimulate antitumor immunity, immunotherapies have revolutionized cancer treatment. However, many patients do not respond initially or develop secondary resistance. Based on the limited resources in the tumor microenvironment and competition between tumor and immune cells, the field of immune metabolism has produced extensive knowledge showing that targeting metabolism could help to modulate antitumor immunity. However, among all the different potentially targetable metabolic pathways, it remains unclear which have more potential to overcome resistance to immune checkpoint inhibitors. Here, we explore metabolic reprogramming in cancer cells, which might inhibit antitumor immunity, and strategies that can be used to favor the antitumor response.

scholarly journals A Holistic Perspective: Exosomes Shuttle between Nerves and Immune Cells in the Tumor Microenvironment

2020 ◽  
Vol 9 (11) ◽  
pp. 3529
Author(s):  
Mihnea P. Dragomir ◽  
Vlad Moisoiu ◽  
Roxana Manaila ◽  
Barbara Pardini ◽  
Erik Knutsen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Systemic Disease ◽  
Improved Outcomes ◽  
Complex Landscape ◽  
Endothelial Growth Factor

One of the limitations of cancer research has been the restricted focus on tumor cells and the omission of other non-malignant cells that are constitutive elements of this systemic disease. Current research is focused on the bidirectional communication between tumor cells and other components of the tumor microenvironment (TME), such as immune and endothelial cells, and nerves. A major success of this bidirectional approach has been the development of immunotherapy. Recently, a more complex landscape involving a multi-lateral communication between the non-malignant components of the TME started to emerge. A prime example is the interplay between immune and endothelial cells, which led to the approval of anti-vascular endothelial growth factor-therapy combined with immune checkpoint inhibitors and classical chemotherapy in non-small cell lung cancer. Hence, a paradigm shift approach is to characterize the crosstalk between different non-malignant components of the TME and understand their role in tumorigenesis. In this perspective, we discuss the interplay between nerves and immune cells within the TME. In particular, we focus on exosomes and microRNAs as a systemic, rapid and dynamic communication channel between tumor cells, nerves and immune cells contributing to cancer progression. Finally, we discuss how combinatorial therapies blocking this tumorigenic cross-talk could lead to improved outcomes for cancer patients.

scholarly journals The Metabolism Symbiosis Between Pancreatic Cancer and Tumor Microenvironment

2021 ◽  
Vol 11 ◽  
Author(s):  
Ying Li ◽  
Ju Zhang ◽  
Jie Xu ◽  
Shanglong Liu
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Tumor Therapy ◽  
Tumor Development ◽  
Metabolic Reprogramming ◽  
Metabolic Adaptation ◽  
Metabolic Pattern ◽  
New Approach ◽  
Complex Interactions ◽  
Selective Targeting

Complex interactions occur between tumor cells and the tumor microenvironment. Studies have focused on the mechanism of metabolic symbiosis between tumors and the tumor microenvironment. During tumor development, the metabolic pattern undergoes significant changes, and the optimal metabolic mode of the tumor is selected on the basis of its individual environment. Tumor cells can adapt to a specific microenvironment through metabolic adjustment to achieve compatibility. In this study, the effects of tumor glucose metabolism, lipid metabolism, and amino acid metabolism on the tumor microenvironment and related mechanisms were reviewed. Selective targeting of tumor cell metabolic reprogramming is an attractive direction for tumor therapy. Understanding the mechanism of tumor metabolic adaptation and determining the metabolism symbiosis mechanism between tumor cells and the surrounding microenvironment may provide a new approach for treatment, which is of great significance for accelerating the development of targeted tumor metabolic drugs and administering individualized tumor metabolic therapy.

scholarly journals Metabolism of Immune Cells in the Tumor Microenvironment

2021 ◽  
pp. 173-185
Author(s):  
Jin G. Jung ◽  
Anne Le
Keyword(s):  
Extracellular Matrix ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Immune Cells ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Determinant Factor

AbstractThe tumor microenvironment (TME) is a complex biological structure surrounding tumor cells and includes blood vessels, immune cells, fibroblasts, adipocytes, and extracellular matrix (ECM) [1, 2]. These heterogeneous surrounding structures provide nutrients, metabolites, and signaling molecules to provide a cancer-friendly environment. The metabolic interplay between immune cells and cancer cells in the TME is a key feature not only for understanding tumor biology but also for discovering cancer cells’ vulnerability. As cancer immunotherapy to treat cancer patients and the use of metabolomics technologies become more and more common [3], the importance of the interplay between cancer cells and immune cells in the TME is emerging with respect to not only cell-to-cell interactions but also metabolic pathways. This interaction between immune cells and cancer cells is a complex and dynamic process in which immune cells act as a determinant factor of cancer cells’ fate and vice versa. In this chapter, we provide an overview of the metabolic interplay between immune cells and cancer cells and discuss the therapeutic opportunities as a result of this interplay in order to define targets for cancer treatment. It is important to understand and identify therapeutic targets that interrupt this cancerpromoting relationship between cancer cells and the surrounding immune cells, allowing for maximum efficacy of immune checkpoint inhibitors as well as other genetic and cellular therapies.

scholarly journals Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies

2021 ◽  
Vol 11 ◽  
Author(s):  
Guofeng Ma ◽  
Chun Li ◽  
Zhilei Zhang ◽  
Ye Liang ◽  
Zhijuan Liang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Escape ◽  
Tumor Therapy ◽  
Checkpoint Blockade ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Tumor Immune Escape ◽  
New Era ◽  
Cell Expression

Immunotherapy, especially PD-1/PD-L1 checkpoint blockade immunotherapy, has led tumor therapy into a new era. However, the vast majority of patients do not benefit from immunotherapy. One possible reason for this lack of response is that the association between tumors, immune cells and metabolic reprogramming in the tumor microenvironment affect tumor immune escape. Generally, the limited amount of metabolites in the tumor microenvironment leads to nutritional competition between tumors and immune cells. Metabolism regulates tumor cell expression of PD-L1, and the PD-1/PD-L1 immune checkpoint regulates the metabolism of tumor and T cells, which suggests that targeted tumor metabolism may have a synergistic therapeutic effect together with immunotherapy. However, the targeting of different metabolic pathways in different tumors may have different effects on tumor immune escape. Herein, we discuss the influence of glucose metabolism and glutamine metabolism on tumor immune escape and describe the theoretical basis for strategies targeting glucose or glutamine metabolism in combination with PD-1/PD-L1 checkpoint blockade immunotherapy.

scholarly journals Depleting Tumor Cells Expressing Immune Checkpoint Ligands—A New Approach to Combat Cancer

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 872
Author(s):  
Fabrizio Marcucci ◽  
Cristiano Rumio
Keyword(s):  
Tumor Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Epithelial Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
Tumor Therapy ◽  
Treatment Protocols ◽  
Mesenchymal Transition ◽  
Effector Functions ◽  
Tumor Types

Antibodies against inhibitory immune checkpoint molecules (ICPMs), referred to as immune checkpoint inhibitors (ICIs), have gained a prominent place in cancer therapy. Several ICIs in clinical use have been engineered to be devoid of effector functions because of the fear that ICIs with preserved effector functions could deplete immune cells, thereby curtailing antitumor immune responses. ICPM ligands (ICPMLs), however, are often overexpressed on a sizeable fraction of tumor cells of many tumor types and these tumor cells display an aggressive phenotype with changes typical of tumor cells undergoing an epithelial-mesenchymal transition. Moreover, immune cells expressing ICPMLs are often endowed with immunosuppressive or immune-deviated functionalities. Taken together, these observations suggest that compounds with the potential of depleting cells expressing ICPMLs may become useful tools for tumor therapy. In this article, we summarize the current state of the art of these compounds, including avelumab, which is the only ICI targeting an ICPML with preserved effector functions that has gained approval so far. We also discuss approaches allowing to obtain compounds with enhanced tumor cell-depleting potential compared to native antibodies. Eventually, we propose treatment protocols that may be applied in order to optimize the therapeutic efficacy of compounds that deplete cells expressing ICPMLs.

scholarly journals Novel immune checkpoints beyond PD-1 in advanced melanoma

2021 ◽  
Author(s):  
Nina Zila ◽  
Christoph Hoeller ◽  
Verena Paulitschke
Keyword(s):  
Clinical Trials ◽  
Checkpoint Inhibitors ◽  
Short Review ◽  
Therapy Resistance ◽  
Advanced Melanoma ◽  
Immune Checkpoints ◽  
Malignant Diseases ◽  
Foreseeable Future ◽  
Cell Responses ◽  
Therapeutic Landscape

SummaryIn malignant diseases, targeting of immune checkpoints successfully changed the therapeutic landscape and helped to unleash anti-tumor T cell responses, resulting in durable clinical outcomes, but only in up to 50% of patients. The success of these therapies and the need to overcome intrinsic and acquired therapy resistance stimulated research to identify new pathways and targets. Numerous clinical trials are currently evaluating novel checkpoint inhibitors or recently developed strategies like modulating the tumor microenvironment, mostly in combination with approved therapies. This short review briefly discusses promising therapeutic targets, currently still under investigation, with the chance to realize clinical application in the foreseeable future.

scholarly journals From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2278
Author(s):  
Afshin Derakhshani ◽  
Zeinab Rostami ◽  
Hossein Safarpour ◽  
Mahdi Abdoli Shadbad ◽  
Niloufar Sadat Nourbakhsh ◽  
...  
Keyword(s):  
Single Cell ◽  
Signaling Pathways ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cancer Development ◽  
Immune Checkpoints ◽  
Single Cell Sequencing ◽  
Increased Risk

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

Sign in / Sign up

Export Citation Format

Share Document