Pivotal role of PD-1/PD-L1 immune checkpoints in immune escape and cancer progression: their interplay with platelets and FOXP3+Tregs related molecules, clinical implications and combinational potential with phytochemicals

Lung cancer is the leading cause of cancer deaths worldwide. Immunotherapies (IT) have been rapidly approved for lung cancer treatment after the spectacular results in melanoma. Responses to the currently used checkpoint inhibitors are strikingly good especially in metastatic diseases. However, durable responses are observed in only 25% of cases. Consequently, there is an urgent need for new immunotherapy targets. Among the multiple checkpoints involved in the tumor immune escape, the BTLA-HVEM couple appears to be a promising target. BTLA (B- and T- Lymphocyte Attenuator) is a co-inhibitory receptor mainly expressed by B and T cells, repressing the activation signal transduction. BTLA shares similarities with other immune checkpoints such as PD-1 and CTLA-4 which are the targets of the currently used immunotherapies. Furthermore, BTLA expression points out terminally exhausted and dysfunctional lymphocytes, and correlates with lung cancer progression. The ligand of BTLA is HVEM (Herpes Virus Entry Mediator) which belongs to the TNF receptor family. Often described as a molecular switch, HVEM is constitutively expressed by many cells, including cells from tumor and healthy tissues. In addition, HVEM seems to be involved in tumor immuno-evasion, especially in lung tumors lacking PD-L1 expression. Here, we propose to review the role of BTLA-HVEM in immuno-escape in order to highlight its potential for designing new immunotherapies.

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Spatial genomics maps the structure, character and evolution of cancer clones

10.1101/2021.04.16.439912 ◽

2021 ◽

Author(s):

Artem Lomakin ◽

Jessica Svedlund ◽

Carina Strell ◽

Milana Gataric ◽

Artem Shmatko ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Outcome ◽

Data Integration ◽

Cancer Progression ◽

Lineage Tracing ◽

Breast Cancer Progression ◽

Pivotal Role ◽

Universal Feature

Subclonality is a universal feature of cancers yet how clones grow, are spatially organised, differ phenotypically or influence clinical outcome is unclear. To address this, we developed base specific in situ sequencing (BaSISS). In fixed tissues, transcripts harbouring clone-defining mutations are detected, converted into quantitative clone maps and characterised through multi-layered data integration. Applied to 8 samples from key stages of breast cancer progression BaSISS localised 1.42 million genotype informative transcripts across 4.9cm2 of tissue. Microscopic clonal topographies are shaped by resident tissue architectures. Distinct transcriptional, histological and immunological features distinguish coexistent genetic clones. Spatial lineage tracing temporally orders clone features associated with the emergence of aggressive clinical traits. These results highlight the pivotal role of spatial genomics in deciphering the mechanisms underlying cancer progression.

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Pivotal role of human stearoyl-CoA desaturases (SCD1 and 5) in breast cancer progression: oleic acid-based effect of SCD1 on cell migration and a novel pro-cell survival role for SCD5

Oncotarget ◽

10.18632/oncotarget.25273 ◽

2018 ◽

Vol 9 (36) ◽

pp. 24364-24380 ◽

Cited By ~ 18

Author(s):

Cristiana Angelucci ◽

Alessio D’Alessio ◽

Fortunata Iacopino ◽

Gabriella Proietti ◽

Alba Di Leone ◽

...

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Oleic Acid ◽

Cell Survival ◽

Cancer Progression ◽

Breast Cancer Progression ◽

Pivotal Role

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The Role of Chemokines in Cervical Cancers

Medicina ◽

10.3390/medicina57111141 ◽

2021 ◽

Vol 57 (11) ◽

pp. 1141

Author(s):

Fabian Garrido ◽

Carl Mathis Wild ◽

Johanna Mittelberger ◽

Franziska Dobler ◽

Mariella Schneider ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Progression ◽

Immune Checkpoint ◽

Cervical Dysplasia ◽

Experimental Studies ◽

Immune Checkpoints ◽

Clear Understanding ◽

Cervical Cancers ◽

Therapy Development

Both clinical-pathological and experimental studies have shown that chemokines play a key role in activating the immune checkpoint modulator in cervical cancer progression and are associated with prognosis in tumor cell proliferation, invasion, angiogenesis, chemoresistance, and immunosuppression. Therefore, a clear understanding of chemokines and immune checkpoint modulators is essential for the treatment of this disease. This review discusses the origins and categories of chemokines and the mechanisms that are responsible for activating immune checkpoints in cervical dysplasia and cancer, chemokines as biomarkers, and therapy development that targets immune checkpoints in cervical cancer research.

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Extracellular Vesicles and Tumor-Immune Escape: Biological Functions and Clinical Perspectives

International Journal of Molecular Sciences ◽

10.3390/ijms21072286 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2286 ◽

Cited By ~ 8

Author(s):

Stefania Raimondo ◽

Marzia Pucci ◽

Riccardo Alessandro ◽

Simona Fontana

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Immune Cell ◽

Immune Escape ◽

Immune Checkpoints ◽

Cancer Therapies ◽

Biological Functions ◽

Hallmarks Of Cancer ◽

Tumor Immune Escape

The modulation of the immune system is one of the hallmarks of cancer. It is now widely described that cancer cells are able to evade the immune response and thus establish immune tolerance. The exploration of the mechanisms underlying this ability of cancer cells has always attracted the scientific community and is the basis for the development of new promising cancer therapies. Recent evidence has highlighted how extracellular vesicles (EVs) represent a mechanism by which cancer cells promote immune escape by inducing phenotypic changes on different immune cell populations. In this review, we will discuss the recent findings on the role of tumor-derived extracellular vesicles (TEVs) in regulating immune checkpoints, focusing on the PD-L1/PD-1 axis.

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Pain and Attention

10.1093/oso/9780190627898.003.0006 ◽

2018 ◽

Author(s):

Dimiti van Ryckeghem ◽

Geert Crombez

Keyword(s):

Contextual Factors ◽

Critical Role ◽

Daily Activities ◽

Pivotal Role ◽

Future Research ◽

Clinical Implications ◽

Top Down ◽

Theoretical Frameworks ◽

The Relationship

Attention plays a pivotal role in the experience of pain and its impact upon daily activities. Accordingly, research on the interplay between attention and pain has a long scientific history. This chapter discusses the theoretical frameworks that aim to explain the relationship between attention and pain. It argues for a motivational perspective on pain that highlights the critical role of cognitive, affective, and contextual factors in explaining the interplay between attention and pain. To substantiate this argument, the chapter provides an overview of available research addressing the bottom-up capture of attention by pain and the top-down modulation (both inhibition and facilitation) of attention for pain. It concludes with guidelines and suggestions for future research and discusses clinical implications of adopting a motivational perspective on pain.

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Pan-Cancer Analysis Shows Enrichment of Macrophages, Overexpression of Checkpoint Molecules, Inhibitory Cytokines, and Immune Exhaustion Signatures in EMT-High Tumors

Frontiers in Oncology ◽

10.3389/fonc.2021.793881 ◽

2022 ◽

Vol 11 ◽

Author(s):

Jayesh Kumar Tiwari ◽

Shloka Negi ◽

Manju Kashyap ◽

Sheikh Nizamuddin ◽

Amar Singh ◽

...

Keyword(s):

Cancer Progression ◽

Immune Escape ◽

The Cancer Genome Atlas ◽

Mesenchymal Transition ◽

Gene Signatures ◽

Immune Exhaustion ◽

Cancer Types ◽

Tcga Dataset ◽

Pan Cancer

Epithelial–mesenchymal transition (EMT) is a highly dynamic process that occurs under normal circumstances; however, EMT is also known to play a central role in tumor progression and metastasis. Furthermore, role of tumor immune microenvironment (TIME) in shaping anticancer immunity and inducing the EMT is also well recognized. Understanding the key features of EMT is critical for the development of effective therapeutic interventions. Given the central role of EMT in immune escape and cancer progression and treatment, we have carried out a pan-cancer TIME analysis of The Cancer Genome Atlas (TCGA) dataset in context to EMT. We have analyzed infiltration of various immune cells, expression of multiple checkpoint molecules and cytokines, and inflammatory and immune exhaustion gene signatures in 22 cancer types from TCGA dataset. A total of 16 cancer types showed a significantly increased (p < 0.001) infiltration of macrophages in EMT-high tumors (mesenchymal samples). Furthermore, out of the 17 checkpoint molecules we analyzed, 11 showed a significant overexpression (p < 0.001) in EMT-high samples of at least 10 cancer types. Analysis of cytokines showed significant enrichment of immunosuppressive cytokines—TGFB1 and IL10—in the EMT-high group of almost all cancer types. Analysis of various gene signatures showed enrichment of inflammation, exhausted CD8+ T cells, and activated stroma signatures in EMT-high tumors. In summary, our pan-cancer EMT analysis of TCGA dataset shows that the TIME of EMT-high tumors is highly immunosuppressive compared to the EMT-low (epithelial) tumors. The distinctive features of EMT-high tumors are as follows: (i) the enrichment of tumor-associated macrophages, (ii) overexpression of immune checkpoint molecules, (iii) upregulation of immune inhibitory cytokines TGFB1 and IL10, and (iv) enrichment of inflammatory and exhausted CD8+ T-cell signatures. Our study shows that TIMEs of different EMT groups differ significantly, and this would pave the way for future studies analyzing and targeting the TIME regulators for anticancer immunotherapy.

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Human Galectin-1 and Its Inhibitors: Privileged Target for Cancer and HIV

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666190304120821 ◽

2019 ◽

Vol 19 (16) ◽

pp. 1369-1378 ◽

Cited By ~ 6

Author(s):

Narella Sridhar Goud ◽

P.S. Lakshmi Soukya ◽

Mahammad Ghouse ◽

Daipule Komal ◽

Ravi Alvala ◽

...

Keyword(s):

Cancer Progression ◽

Viral Entry ◽

Immune Escape ◽

Specific Binding ◽

Therapeutic Approaches ◽

Therapeutic Drugs ◽

Kinetics Of ◽

Structural Insights ◽

Hiv 1

Galectin 1(Gal-1), a β-galactoside binding mammalian lectin of 14KDa, is implicated in many signalling pathways, immune responses associated with cancer progression and immune disorders. Inhibition of human Gal-1 has been regarded as one of the potential therapeutic approaches for the treatment of cancer, as it plays a major role in tumour development and metastasis by modulating various biological functions viz. apoptosis, angiogenesis, migration, cell immune escape. Gal-1 is considered as a biomarker in diagnosis, prognosis and treatment condition. The overexpression of Gal-1 is well established and seen in many types of cancer progression like osteosarcoma, breast, lung, prostate, melanoma, etc. Gal-1 greatly accelerates the binding kinetics of HIV-1 to susceptible cells, leading to faster viral entry and a more robust viral replication by specific binding of CD4 cells. Hence, the Gal-1 is considered a promising molecular target for the development of new therapeutic drugs for cancer and HIV. The present review laid emphasis on structural insights and functional role of Gal-1 in the disease, current Gal-1 inhibitors and future prospects in the design of specific Gal-1 inhibitors.

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The metabolic milieu in melanoma: Role of immune suppression by CD73/adenosine

Tumor Biology ◽

10.1177/1010428319837138 ◽

2019 ◽

Vol 41 (4) ◽

pp. 101042831983713 ◽

Cited By ~ 8

Author(s):

Anna Passarelli ◽

Marco Tucci ◽

Francesco Mannavola ◽

Claudia Felici ◽

Francesco Silvestris

Keyword(s):

Immune Suppression ◽

Immune Escape ◽

Prognostic Biomarker ◽

Therapeutic Strategies ◽

The Other ◽

Immune Checkpoints ◽

Receptor Signalling ◽

Promising Therapeutic Target ◽

Translational Strategies

The mechanisms leading to immune escape of melanoma have been largely investigated in relation to its tumour immunogenicity and features of inflamed microenvironment that promote the immune suppression during the disease progression. These findings have recently led to advantages in terms of immunotherapy-based approaches as rationale for overcoming the immune escape. However, besides immune checkpoints, other mechanisms including the adenosine produced by ectonucleotidases CD39 and CD73 contribute to the melanoma progression due to the immunosuppression induced by the tumour milieu. On the other hand, CD73 has recently emerged as both promising therapeutic target and unfavourable prognostic biomarker. Here, we review the major mechanisms of immune escape activated by the CD39/CD73/adenosine pathway in melanoma and focus potential therapeutic strategies based on the control of CD39/CD73 downstream adenosine receptor signalling. These evidences provide the basis for translational strategies of immune combination, while CD73 would serve as potential prognostic biomarker in metastatic melanoma.

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Exosomes in Immune Regulation

Non-Coding RNA ◽

10.3390/ncrna7010004 ◽

2021 ◽

Vol 7 (1) ◽

pp. 4

Author(s):

Heidi Schwarzenbach ◽

Peter B. Gahan

Keyword(s):

Immune System ◽

Tumor Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Immune Cells ◽

Intercellular Communication ◽

Immune Regulation ◽

Immune Escape ◽

Cytotoxic Responses

Exosomes, small extracellular vesicles mediate intercellular communication by transferring their cargo including DNA, RNA, proteins and lipids from cell to cell. Notably, in the immune system, they have protective functions. However in cancer, exosomes acquire new, immunosuppressive properties that cause the dysregulation of immune cells and immune escape of tumor cells supporting cancer progression and metastasis. Therefore, current investigations focus on the regulation of exosome levels for immunotherapeutic interventions. In this review, we discuss the role of exosomes in immunomodulation of lymphoid and myeloid cells, and their use as immune stimulatory agents to elicit specific cytotoxic responses against the tumor.

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