What's The Future of Cancer Immunotherapy? World Renowned Cancer Expert Shares His Perspective

curncman
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The epithelial-mesenchymal transcription factor SNAI1 represses transcription of the tumor suppressor miRNA let-7 in can

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The epithelial-mesenchymal transcription factor SNAI1 represses transcription of the tumor suppressor miRNA let-7 in cancer

https://www.biorxiv.org/content/10.1101 ... 88v1?rss=1

Abstract
We aimed to determine the mechanism of epithelial-mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.
curncman
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Supercharging the Immune System: The Future of Cancer Care

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Supercharging the Immune System: The Future of Cancer Care

https://uahs.arizona.edu/blog/2018-06-1 ... ancer-care

Most people familiar with cancer treatment know of three main options: surgery, radiation and chemotherapy. But a newer option, called immunotherapy, is creating quite a buzz across the cancer community.

These drugs teach the immune system how to recognize and kill cancer cells, equipping it to home in on diseased cells while leaving healthy cells alone.

Immunotherapy comes in many “flavors.” Some you may have heard of, like vaccines and bone marrow transplants. But other types are even more cutting-edge.

“Now we’re in the era of cellular immunotherapy,” says Daniel Persky, MD, director of the University of Arizona Cancer Center Clinical Trials Office. “We’re using cells, particularly T cells, which are being retrained or redesigned to fight cancers more directly.”

CAR T cells are a form of cellular immunotherapy that gained media attention and public excitement as the first cancer treatments to alter a patient’s genes. In 2017, the FDA approved two CAR T-cell therapies in quick succession: one for patients with advanced leukemia in August, and a second for patients with large B-cell lymphomas in October.

Researchers have called CAR T cells a “living drug” because they modify a patient’s own cells to fight disease. First, blood is drawn from the patient and sent to a lab. Here, T cells are separated from the blood and “supercharged” with a gene that generates chimeric antigen receptors (CAR), which allow the T cells to bind to cancer cells and destroy them. Hundreds of millions of these T cells are synthesized in the laboratory to create a personalized, well-armed immune defense. Finally, the patient’s newly educated T cells are returned to the clinic and reinfused into the patient, seeking and destroying cancer cells in the patient’s bloodstream.

In general, immunotherapy drugs are not frequently used in pediatric populations. CAR T cells are an exception.

“CAR T cells are used to treat acute lymphoblastic leukemia, which is very common in kids,” says Emmanuel Katsanis, MD, director of the UA Cancer Center Blood and Marrow Transplantation Program.

This therapy provides a safety net for patients whose cancers return even after standard treatments.

“Bone marrow transplant still offers a cure for 75 to 80 percent of patients with acute lymphoblastic leukemia,” says Dr. Katsanis. “CAR T cells currently are reserved for patients who relapse, usually after bone marrow transplant.”

Dr. Persky is excited that the UA Cancer Center will be one of the first sites in the state to offer CAR T-cell therapy.

“We’re bringing clinical trials with CAR T-cell therapy here,” reports Dr. Persky. “We will also be opening our cancer center to standard-of-care CAR T cells.”

In the future, additional research will reveal whether CAR T cells can be aimed at solid tumors like breast and colorectal cancers. The addition of further CAR T-cell therapies to the list of approved treatments also will help patients whose cancers have relapsed. With more research, trials and FDA approvals, the future of cancer treatment is only getting brighter.

Learn more about the promise of immunotherapy in the recent issue of Act Against Cancer, in which UA Cancer Center physicians and scientists discuss their work in this exciting new field.
curncman
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Sepsis 'could be stopped by injecting patients with turbocharged blood cells' which boost the immune system of patients

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Sepsis 'could be stopped by injecting patients with turbocharged blood cells' which boost the immune system of patients with the deadly illness
Scientists at Ohio State University tested their therapy successfully on mice
They hoped it could be used for people in late-stage sepsis, which is often fatal
The treatment worked by genetically engineering a donor's white blood cells
People with sepsis don't have enough of their own and they may malfunction

https://www.dailymail.co.uk/health/arti ... epsis.html
curncman
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COVID-19 and the Immune System: How Cancer Research Can Help Rein in the Novel Coronavirus Pandemic

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COVID-19 and the Immune System: How Cancer Research Can Help Rein in the Novel Coronavirus Pandemic

https://www.cancerresearch.org/blog/mar ... r-research
curncman
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The yin-yang of the interaction between myelomonocytic cells and NK cells

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The yin-yang of the interaction between myelomonocytic cells and NK cells


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485394/

Abstract
NK cells are innate lymphoid cells, which play a key role in the immune response to cancer and pathogens and participate in the shaping of adaptive immunity. NK cells engage in a complex bidirectional interaction with myelomonocytic cells. In particular, macrophages, dendritic cells and neutrophils promote differentiation and effector function of NK cells and, on the other hand, myelomonocytic cells express triggers of checkpoint blockade (e.g. PD-L1) and other immunosuppressive molecules, which negatively regulate NK cell function. In addition, NK cells express high levels of IL-1R8, which acts as a checkpoint for IL-18 driven differentiation and activation of NK cells. Evidence suggests that targeting the myeloid cell-NK cell crosstalk unleashes effective antitumor and antiviral resistance.

Conclusions
NK cells are innate lymphoid cells with cytotoxic potential against cancer or virally infected cells. Engagement of various activating and inhibitory receptors on the NK cell with ligands present on the target cell surface, initiates balanced signalling pathways leading to NK cell function or tolerance. In addition, NK cells engage bidirectional interactions with other leukocytes, including macrophages, DCs and neutrophils, which affect both cell types. Macrophage-NK cell crosstalk is an important component of the immune response against microbes and cancer. In particular, in type 1-oriented immune responses, NK cells amplify both innate and adaptive responses, as a result of their interaction with M1-polarized macrophages. Although NK cells are spontaneously cytotoxic innate lymphocytes, the interaction with DCs and trans-presented cytokines has been identified as a crucial mechanism leading to NK cell priming and full activation. Similarly, the interaction between NK cells and neutrophils through soluble mediators and adhesion molecules, influences NK cell maturation and responsiveness, as well as neutrophil survival. In addition to IL-12 and IL-15, IL-18 is emerging as a key myeloid cell-derived factor involved in the activation of NK cells. IL-18 activity is tightly regulated by IL-1R8, a negative regulator of the IL-1 receptor family, acting as a novel checkpoint of the anti-viral and anti-tumor functions of NK cells, both against primary liver tumors and metastasis. In a translational perspective, these bidirectional interactions with phagocytes, myeloid-derived factors and their regulation must be taken into account to fully exploit the potential of NK cells to restrain primary cancer and metastasis.
curncman
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Consequences of the crosstalk between monocytes/macrophages and natural killer cells. Front

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Consequences of the crosstalk between monocytes/macrophages and natural killer cells. Front

https://www.researchgate.net/publicatio ... ells_Front

Abstract and Figures
The interaction between natural killer (NK) cells and different other immune cells like T cells and dendritic cells is well-described, but the crosstalk with monocytes or macrophages and the nature of ligands/receptors implicated are just emerging. The macrophage-NK interaction is a major first-line defense against pathogens (bacteria, viruses, fungi, and parasites). The recruitment and the activation of NK cells to perform cytotoxicity or produce cytokines at the sites of inflammation are important to fight infections. The two main mechanisms by which macrophages can prime NK cells are (1) activation through soluble mediators such as IL-12, IL-18, and (2) stimulation through direct cell-to-cell contact. We will discuss the progress in matters of modulation of NK cell functions by monocytes and macrophages, in the steady state and during diseases.

CONCLUDING REMARKSActi vation of NK c ells by many pathogens is triggered in part bysignals coming from macrophages. The precise molecular inter-actions that underlie macrophages and NK cell communication need to be further investigated. It will be interesting to betterdefine which implications this crosstalk might have on the adap-tive immune response regarding the complex interactions of thedifferent partners involved.
curncman
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Monocytes and NK Cells Activity in Covid-19 Patients

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https://clinicaltrials.gov/ct2/show/NCT04375176


Immune cells activity [ Time Frame: 6 months ]
Scientists' hypothesis is that monocytes, NK, CD4 AND CD8 T cells, in patients with severe infection to SARS-CoV-2, show an impairment in their function: cells reveal an overpowering hyperactivity that provokes a pathologic inflammatory response with a massive production of proinflammatory cytokine, edema and pulmonary fibrosis.
curncman
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Natural killer cells in cancer biology and therapy

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Natural killer cells in cancer biology and therapy

https://molecular-cancer.biomedcentral. ... 20-01238-x

Abstract
The tumor microenvironment is highly complex, and immune escape is currently considered an important hallmark of cancer, largely contributing to tumor progression and metastasis. Named for their capability of killing target cells autonomously, natural killer (NK) cells serve as the main effector cells toward cancer in innate immunity and are highly heterogeneous in the microenvironment. Most current treatment options harnessing the tumor microenvironment focus on T cell-immunity, either by promoting activating signals or suppressing inhibitory ones. The limited success achieved by T cell immunotherapy highlights the importance of developing new-generation immunotherapeutics, for example utilizing previously ignored NK cells. Although tumors also evolve to resist NK cell-induced cytotoxicity, cytokine supplement, blockade of suppressive molecules and genetic engineering of NK cells may overcome such resistance with great promise in both solid and hematological malignancies. In this review, we summarized the fundamental characteristics and recent advances of NK cells within tumor immunometabolic microenvironment, and discussed potential application and limitations of emerging NK cell-based therapeutic strategies in the era of presicion medicine.

Conclusions and perspectives
In this review, we draw a picture about the development and function of NK cells and emphasize their variant roles in cancer biology. NK cells performed anti-tumor immunity through their interplay with cancer cells, stromal cells and extracellular matrix, especially the metabolites. As tumor metabolism and tumor imunnity are both recent attractive research areas, we summarized relationship between NK cell and metabolism, which may provide ideas for cross study of these areas. NK cells often suffer resistance in TME and possible mechanisms have been illustrated in many researches, thus developing NK cell-based therapeutic strategies. In addition, clinical trials taking advantage of NK cells, either used alone or in combination with other therapies, have achieved promising results, paving the way for the future basic and clinical researches of the previously ignored but now prosperous NK cell-based cancer therapy and lighting up hope for patients resistant to current T cell-based immunotherapy.

Due to the rapid progress in understanding the TME, new concepts of immunotherapy keep emerging, which obviously helps promote the utilization of immune response for the treatment of cancer, especially the long forgotten innate component. Although previously considered to be characterized clearly, recent evidence shows that the accurate processes of differentiation, activation and generation of memory NK cells remain controversial. Most clinical trials related to NK cell immunotherapy are still in phases I and II, and mainly treat hematological malignancies. Although the clinically-proven safety of these drugs is helpful for the clinical transformation of NK treatment methods for solid tumors, which have broader prospect and wider application in the future, difficulties to overcome still exist. A future challenge for the implementation of NK cell-based therapy is to better define specific NK cell populations and to identify respective markers, as well as functional and regulatory pathways in each subgroup, thereby using different therapeutic strategies for the treatment of tumors infiltrated with different NK cells. Besides, to avoid off-target effects exerted by established anti-tumor drugs on the microenvironment to inhibit treatment effectiveness, more carefully selected combination therapies should be implemented in future clinical trials.

As most studies now take advantage of NK cells originating from blood, trNK cells are worth further investigating for implication in adoptive cell therapy especially for solid tumors. In the era of precision medicine, defining these questions could prompt new approaches that would permit selective regulation of anti-tumor versus pro-tumor response of NK cells. It is an exciting moment in which attention should be paid to this long-ignored cell population, and future possible targets for improved treatment options may harness tumor intrinsic pathways involving both extrinsic innate and adaptive immunity-related microenvironment.
curncman
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11.3F: Natural Killer Cells (NK Cells) and Invariant Natural Killer T-Lymphocytes (iNKT Cells)

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11.3F: Natural Killer Cells (NK Cells) and Invariant Natural Killer T-Lymphocytes (iNKT Cells)

https://bio.libretexts.org/Bookshelves/ ... NKT_Cells)


Learning Objectives

Describe how NK cells are able to recognize and kill infected cells and cancer cells lacking MHC-I molecules.
State two factors that can result in a nucleated human cell not producing MHC-I molecules.
State how iNKT cells recognize glycolipids in order to become activated.
Describe the overall function of iNKT cells in terms how they promote both innate and adaptive immunity and may also help to regulate the immune responses.

Natural Killer Cells (NK Cells)
NK cells are important in innate immunity because they are able to recognize infected cells, cancer cells, and stressed cells and kill them. In addition, they produce a variety of cytokines, including proinflammatory cytokines, chemokines, colony-stimulating factors, and other cytokines that function as regulators of body defenses. For example, through cytokine production NK cells also suppress and/or activate macrophages , suppress and/or activate the antigen-presenting capabilities of dendritic cells, and suppress and/or activate T-lymphocyte responses.

NK cells use a dual receptor system in determining whether to kill or not kill human cells. When cells are either under stress, are turning into tumors, or are infected, various stress-induced molecules such as MHC class I polypeptide-related sequence A (MICA) and MHC class I polypeptide-related sequence B (MICB) are produced and are put on the surface of that cell.

The first receptor, called the killer-activating receptor, can bind to these stress-induced molecules, and this sends a positive signal that enables the NK cell to kill the cell to which it has bound unless the second receptor cancels that signal.

This second receptor, called the killer-ihibitory receptor, recognizes MHC-I molecules that are usually present on all nucleated human cells. MHC-I molecules, produced by all nucleated cells in the body, possess a deep groove that can bind peptides from proteins found within the cytosol of human cells, transport them to the surface of that cell, and display the MHC-!/peptide complex to receptors on cytotoxic T-lymphocytes or CTLs. If the MHC-I molecules have peptides from the body's own proteins bound to them, CTLs do not recognize those cells as foreign and the cell is not killed. If, on the other hand, the MHC-I molecules have peptides from viral, bacterial, or mutant proteins bound to them, CTLs recognize that cell as foreign and kill that cell. (CTLs will be discussed in greater detail in Unit 6.)
curncman
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Natural Killer Cell Dysfunction and Its Role in COVID-19

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https://www.google.com/url?sa=t&rct=j&q ... z0tsGBqddb

5. Conclusions
Natural killer cells play a central role in maintaining immune homeostasis, a critical requirement
when facing the challenge of a novel pathogen. SARS-CoV-2 infection has been shown to impede NK
cell function, thus disrupting this vital balance. With factors such as ageing and other comorbidities,
leading to further skewing, the current trials investigating drugs and biologicals, which improve NK
cell function, may prove to be monumental in our fight against COVID-19.
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