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 Cancer Stem Cell Hypothesis: Implication for Cancer Prevention and Treatment

2016 ◽  
Vol 8 (1) ◽  
pp. 21
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
Cancer Prevention ◽  
Immune Cells ◽  
Epithelial Mesenchymal Transition ◽  
Cell Populations ◽  
Diverse Populations ◽  
Normal Organ ◽  
Mesenchymal Transition ◽  
Multiple Tumor ◽  
Microenvironmental Factors ◽  
Tumor Types

BACKGROUND: Cancer is a disease of genomic instability, evasion of immune cells, and adaptation of the tumor cells to the changing environment. Genetic heterogeneity caused by tumors and tumor microenvironmental factors forms the basis of aggressive behavior of some cancer cell populations.CONTENT: Cancers arise in self-renewing cell populations and that the resulting cancers, like their normal organ counterparts, are composed of hierarchically organized cell populations. Self – renewing “cancer stem cells” (CSC) maintain tumor growth and generate the diverse populations constituting the tumor bulk. CSCs in multiple tumor types have been demonstrated to be relatively resistant to radiation and chemotherapy. The clinical relevance of these studies has been supported by neoadjuvant breast cancer trials that demonstrated increases in the proportions of CSCs after therapy. The CSC hypothesis has tremendously important clinical implications.SUMMARY: In summary, a large and accumulating body of evidence supports the CSC hypothesis, which has important implications for cancer prevention and therapy. The ultimate test of this hypothesis will require clinical trials demonstrating that targeting of these pathways reduces cancer incidence and improves outcomes for patients with cancer.KEYWORDS: Somatic mutation, tumor heterogeneity, metastasis, epithelial-mesenchymal transition, CSC niche

scholarly journals The Vicious Cross-Talk between Tumor Cells with an EMT Phenotype and Cells of the Immune System

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 460 ◽  
Author(s):  
Elisabetta Romeo ◽  
Carmelo Antonio Caserta ◽  
Cristiano Rumio ◽  
Fabrizio Marcucci
Keyword(s):  
Immune System ◽  
Tumor Cells ◽  
Cross Talk ◽  
Immune Cells ◽  
Epithelial Mesenchymal Transition ◽  
Large Body ◽  
Adaptive Immune System ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Immune Exclusion

Carcinoma cells that undergo an epithelial-mesenchymal transition (EMT) and display a predominantly mesenchymal phenotype (hereafter EMT tumor cells) are associated with immune exclusion and immune deviation in the tumor microenvironment (TME). A large body of evidence has shown that EMT tumor cells and immune cells can reciprocally influence each other, with EMT cells promoting immune exclusion and deviation and immune cells promoting, under certain circumstances, the induction of EMT in tumor cells. This cross-talk between EMT tumor cells and immune cells can occur both between EMT tumor cells and cells of either the native or adaptive immune system. In this article, we review this evidence and the functional consequences of it. We also discuss some recent evidence showing that tumor cells and cells of the immune system respond to similar stimuli, activate the expression of partially overlapping gene sets, and acquire, at least in part, identical functionalities such as migration and invasion. The possible significance of these symmetrical changes in the cross-talk between EMT tumor cells and immune cells is addressed. Eventually, we also discuss possible therapeutic opportunities that may derive from disrupting this cross-talk.

scholarly journals Predictive Biomarkers of Immune Checkpoint Inhibitor Response in Breast Cancer: Looking beyond Tumoral PD-L1

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1863
Author(s):  
Nan Chen ◽  
Nicole Higashiyama ◽  
Valentina Hoyos
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Large Scale ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Predictive Biomarkers

Immune checkpoint inhibitors utilize the immune system to kill cancer cells and are now widely applied across numerous malignancies. Pembrolizumab has two breast-specific indications in triple-negative disease. Currently, programmed death ligand-1 (PD-L1) expression on tumor and surrounding immune cells is the only validated predictive biomarker for immune checkpoint inhibitors (ICIs) in breast cancer; however, it can be imprecise. Additional biomarkers are needed to identify the patient population who will derive the most benefit from these therapies. The tumor immune microenvironment contains many biomarker candidates. In tumor cells, tumor mutational burden has emerged as a robust biomarker across malignancies in general, with higher burden cancers demonstrating improved response, but will need further refinement for less mutated cancers. Preliminary studies suggest that mutations in breast cancer gene 2 (BRCA-2) are associated with increased immune infiltration and response to ICI therapy. Other genomic alterations are also being investigated as potential predictive biomarkers. In immune cells, increased quantity of tumor-infiltrating lymphocytes and CD8+ cytotoxic T cells have correlated with response to immunotherapy treatment. The role of other immune cell phenotypes is being investigated. Peripherally, many liquid-based biomarker strategies such as PD-L1 expression on circulating tumor cells and peripheral immune cell quantification are being studied; however, these strategies require further standardization and refinement prior to large-scale testing. Ultimately, multiple biomarkers utilized together may be needed to best identify the appropriate patients for these treatments.

Mesenchymal Stem Cells, Immune Cells and Tumor Cells Crosstalk: A Sinister Triangle in the Tumor Microenvironment

2019 ◽  
Vol 14 (1) ◽  
pp. 43-51 ◽  
Author(s):  
Mahboobeh Razmkhah ◽  
Shabnam Abtahi ◽  
Abbas Ghaderi
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Tumor Cells ◽  
Immune Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Adaptive Immune ◽  
Adaptive Immune Cells

Mesenchymal Stem Cells [MSCs] are a heterogeneous population of fibroblast-like cells which maintain self-renewability and pluripotency. Many studies have demonstrated the immunomodulatory effects of MSCs on the innate and adaptive immune cells. As a result of interactions with tumor cells, microenvironment and immune-stimulating milieu, MSCs contribute to tumor progression by several mechanisms, including sustained proliferative signal in cancer stem cells [CSCs], inhibition of tumor cell apoptosis, transition to tumor-associated fibroblasts [TAFs], promotion of angiogenesis, stimulation of epithelial-mesenchymal transition [EMT], suppression of immune responses, and consequential promotion of tumor metastasis. Here, we present an overview of the latest findings on Janusfaced roles that MSCs play in the tumor microenvironment [TME], with a concise focus on innate and adaptive immune responses.

scholarly journals Context-dependent EMT programs in cancer metastasis

2019 ◽  
Vol 216 (5) ◽  
pp. 1016-1026 ◽  
Author(s):  
Nicole M. Aiello ◽  
Yibin Kang
Keyword(s):  
Tumor Cells ◽  
Cell Fate ◽  
Cancer Metastasis ◽  
Developmental Process ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Adherent Cells ◽  
Mesenchymal Transition ◽  
Functional Consequences ◽  
Tumor Types

Epithelial–mesenchymal transition (EMT) is a developmental process whereby stationary, adherent cells acquire the ability to migrate. EMT is critical for dramatic cellular movements during embryogenesis; however, tumor cells can reactivate EMT programs, which increases their aggressiveness. In addition to motility, EMT is associated with enhanced stem cell properties and drug resistance; thus it can drive metastasis, tumor recurrence, and therapy resistance in the context of cancer. However, the precise requirements for EMT in metastasis have not been fully delineated, with different tumor types relying on discrete EMT effectors. Most tumor cells do not undergo a full EMT, but rather adopt some qualities of mesenchymal cells and maintain some epithelial characteristics. Emerging evidence suggests that partial EMT can drive distinct migratory properties and enhance the epithelial-mesenchymal plasticity of cancer cells as well as cell fate plasticity. This review discusses the diverse regulatory mechanisms and functional consequences of EMT, with an emphasis on the importance of partial EMT.

scholarly journals Variants in Epithelial-Mesenchymal Transition and Immune Checkpoint Genes Are Associated With Immune Cell Profiles and Predict Survival in Non–Small Cell Lung Cancer

2020 ◽  
Vol 144 (10) ◽  
pp. 1234-1244
Author(s):  
Edwin Roger Parra ◽  
Mei Jiang ◽  
Juliana Machado-Rugolo ◽  
Lygia Bertalha Yaegashi ◽  
Tabatha Prieto ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Genetic Variants ◽  
Immune Cell ◽  
Epithelial Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Clinicopathologic Characteristics ◽  
Mesenchymal Transition ◽  
Checkpoint Genes

Context.— Identification of gene mutations that are indicative of epithelial-mesenchymal transition and a noninflammatory immune phenotype may be important for predicting response to immune checkpoint inhibitors. Objective.— To evaluate the utility of multiplex immunofluorescence for immune profiling and to determine the relationships among tumor immune checkpoint and epithelial-mesenchymal transition genomic profiles and the clinical outcomes of patients with nonmetastatic non–small cell lung cancer. Design.— Tissue microarrays containing 164 primary tumor specimens from patients with stages I to IIIA non–small cell lung carcinoma were examined by multiplex immunofluorescence and image analysis to determine the expression of programmed death ligand-1 (PD-L1) on malignant cells, CD68+ macrophages, and cells expressing the immune markers CD3, CD8, CD57, CD45RO, FOXP3, PD-1, and CD20. Immune phenotype data were tested for correlations with clinicopathologic characteristics, somatic and germline genetic variants, and outcome. Results.— A high percentage of PD-L1+ malignant cells was associated with clinicopathologic characteristics, and high density of CD3+PD-1+ T cells was associated with metastasis, suggesting that these phenotypes may be clinically useful to identify patients who will likely benefit from immunotherapy. We also found that ZEB2 mutations were a proxy for immunologic ignorance and immune tolerance microenvironments and may predict response to checkpoint inhibitors. A multivariate Cox regression model predicted a lower risk of death for patients with a high density of CD3+CD45RO+ memory T cells, carriers of allele G of CTLA4 variant rs231775, and those whose tumors do not have ZEB2 mutations. Conclusions.— Genetic variants in epithelial-mesenchymal transition and immune checkpoint genes are associated with immune cell profiles and may predict patient outcomes and response to immune checkpoint blockade.

scholarly journals Avelumab in newly diagnosed glioblastoma

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Francois H Jacques ◽  
Garth Nicholas ◽  
Ian A J Lorimer ◽  
Victorine Sikati Foko ◽  
Jasmine Prevost ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Open Label

Abstract Background Glioblastoma (GBM) is known to use both local and systemic immunosuppressive strategies. One such strategy is the expression of the immune checkpoint protein programmed cell death ligand-1 (PD-L1) by both tumor cells and tumor-associated immune cells. Recent phase III trials using IgG4 antibodies targeting PD-1, the ligand for PD-L1, failed to show any benefit. Avelumab is an IgG1 monoclonal antibody targeting PD-L1. In contrast to the previously tested immune checkpoint inhibitors, it can directly bind tumor cells and immune cells expressing PD-L1 and can induce antibody-dependent cellular cytotoxicity. Methods We conducted a single center, open label, phase II study where avelumab 10 mg/kg IV Q2W was added concurrently to the first monthly temozolomide cycle in patients with newly diagnosed GBM. Immunohistochemical analyses were performed on surgery samples. The primary objective was safety. Secondary objectives were efficacy outcomes according to the immunotherapy Response Assessment in Neuro Oncology criteria, progression free survival (PFS), and overall survival (OS). Exploratory objectives aimed at determining prognostic biomarkers. Results Thirty patients were started on therapy and two were lost to follow-up. Median follow-up time (reverse Kaplan-Meier) was 41.7 months (IQR: 28.3–43.4). Three (10.0%) patients had a related or possibly related treatment emergent adverse event that lead to transient or permanent discontinuation of avelumab. Eight (26.7%) patients had one or more immune-related adverse events, and 8 (26.7%) patients had an infusion-related reaction. The overall response rate was 23.3%, median PFS was 9.7 months, and the median OS was 15.3 months. No pretreatment biomarkers showed any predictive value. Conclusions The addition of avelumab to standard therapy in patients with GBM was not associated with any new safety signal. There was no apparent improvement in OS. Trial Registration NCT03047473 Registered February 9, 2017.

scholarly journals Dual targeting of TGF-β and PD-L1 via a bifunctional anti-PD-L1/TGF-βRII agent: status of preclinical and clinical advances

2020 ◽  
Vol 8 (1) ◽  
pp. e000433 ◽  
Author(s):  
Hanne Lind ◽  
Sofia R Gameiro ◽  
Caroline Jochems ◽  
Renee N. Donahue ◽  
Julius Strauss ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Cells ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
Human Tumor ◽  
Chemotherapeutic Agents ◽  
Human Tumor Cells ◽  
Human Carcinoma ◽  
Mesenchymal Transition

Immunosuppressive entities in the tumor microenvironment (TME) remain a major impediment to immunotherapeutic approaches for a majority of patients with cancer. While the immunosuppressive role of transforming growth factor-β (TGF-β) in the TME is well known, clinical studies to date with anti-TGF-β agents have led to limited success. The bifunctional agent bintrafusp alfa (previously designated M7824) has been developed in an attempt to address this issue. Bintrafusp alfa consists of an IgG1targeting programmed death ligand 1 (PD-L1) moiety fused via peptide linkers to the extracellular domain of two TGF-β receptor II molecules designed to ‘trap’ TGF-β in the TME. This agent is able to bring the TGF-β trap to the TME via its anti-PD-L1 component, thus simultaneously attacking both the immunosuppressive PD-L1 and TGF-β entities. A number of preclinical studies have shown bintrafusp alfa capable of (1) preventing or reverting TGF-β-induced epithelial-mesenchymal transition in human carcinoma cells; this alteration in tumor cell plasticity was shown to render human tumor cells more susceptible to immune-mediated attack as well as to several chemotherapeutic agents; (2) altering the phenotype of natural killer and T cells, thus enhancing their cytolytic ability against tumor cells; (3) mediating enhanced lysis of human tumor cells via the antibody-dependent cell-mediated cytotoxicity mechanism; (4) reducing the suppressive activity of Tregcells; (5) mediating antitumor activity in numerous preclinical models and (6) enhancing antitumor activity in combination with radiation, chemotherapy and several other immunotherapeutic agents. A phase I clinical trial demonstrated a safety profile similar to other programmed cell death protein 1 (PD-1)/PD-L1 checkpoint inhibitors, with objective and durable clinical responses. We summarize here preclinical and emerging clinical data in the use of this bispecific and potentially multifunctional agent.

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 Advances in Molecular Mechanisms and Immunotherapy Involving the Immune Cell-Promoted Epithelial-to-Mesenchymal Transition in Lung Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Serena De Matteis ◽  
Matteo Canale ◽  
Alberto Verlicchi ◽  
Giuseppe Bronte ◽  
Angelo Delmonte ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
New Combination ◽  
Immune Checkpoints ◽  
Mesenchymal Transition

Immunotherapy has offered a new opportunity for the treatment of many malignancies. In patients with lung cancer, immune checkpoint inhibitors have significantly improved survival. However, little is known about predictive factors or primary and acquired resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is a complex of phenotypic changes involved in carcinogenesis and resistance to cancer treatments. Specifically, immune cells in the tumor microenvironment can promote EMT, and mesenchymal phenotype acquisition negatively regulates the anticancer immune response. EMT is associated with higher expression of PD-L1 and other immune checkpoints. In this review, we focused on the role of EMT in the interplay between tumor cells and the immune system, with particular emphasis on lung cancer. On the basis of our findings, we hypothesize that the effects of EMT on immune cells could be overcome in this disease by a new combination of immune checkpoint inhibitors.

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