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

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

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I want to share this with you from one of our members of our scientific advisory board at TSOI, Dr. Francesco Marincola. This is his current bio at Refuge Biotech where he is currently Chief Scientific Officer, President

Francesco Marincola, M.D.
Chief Scientific Officer, President
Dr. Marincola leads development of Refuge’s intelligent cell therapy platform and investigation of its lead therapeutic programs. He most recently served as a distinguished research fellow and strategist for immune oncology discovery at AbbVie. Prior to this, he developed and led a genetic research institute at Sidra Medical and Research Center in Qata where he played a pivotal role in the Qatar Genome Project. He also trained in surgical oncology under Steven Rosenberg, M.D., Ph.D., at the National Cancer Institute and subsequently was a tenured investigator and chief of the infectious disease and immunogenetics section at the NIH Clinical Center. Dr. Marincola has spent his career studying tumor immunology and was a pioneer in the development of technologies for studying in real-time the dynamics of the tumor microenvironment adaptations during immune therapy. He described the mechanisms leading to cancer immune rejection describing the immunologic constant of rejection as a conserved process shared responsible for other forms of immune-mediated tissue-specific destruction such as allograft rejection, graft versus host disease, flares of autoimmunity and clearance of pathogen during acute infections. He is currently leading worldwide efforts to understand the mechanism of cancer immune resistance such as the Society for the Immunotherapy of Cancer Task Force on Immune Responsiveness aimed at involving different areas of expertise besides immunology. Dr. Marincola graduated summa cum laude at the University of Milan, Medical School, Italy, and completed a general surgery residency with a focus in immunology at Stanford University. He was president of the Society for the Immunotherapy of Cancer and is the founding and current editor-in-chief of the Journal of Translational Medicine.

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

Post by TimGDixon »

Franco is the pioneer of the first FDA approved immunotherapy IL-2 (interleukin 2) and this video he discusses it in lenght. The claim below is from our granted and issued patent 9,682,047

Augmentation of oncology immunotherapies by pterostilbene containing compositions

Abstract

Compositions and methods useful to enhancing, improving, or eliciting anti-tumor immune responses are disclosed. A pterostilbene containing composition is administered to a cancer patient at a sufficient concentration and frequency to induce de-repression of tumor targeting immune responses. The composition enhances antibody dependent cellular toxicity (ADCC) and augments efficacy of antigen specific immunotherapeutics such as trastuzumab and other monoclonal antibody therapies useful for treating cancer.

What is claimed is:
1. A method of treating cancer in a subject, comprising:
selecting a subject having a cancerous tumor; and administering to the subject a composition comprising an effective amount of pterostilbene and IL-2.
nathanflannigam
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Re: What's The Future of Cancer Immunotherapy? World Renowned Cancer Expert Shares His Perspective

Post by nathanflannigam »

Congratulations on working with one of the top Immunologists in the world. Did you know that Francesco (Franco) Marincola is considered the Father of Immunotherpy? He is right up there with Nick Restifo and Steve Rosenburg.

$TSOI stock is extremely exciting because of the fundamentals which the company possesses. They have scientific greats like James Veltmeyer and Tim Dixon, they have an incredible patent portfolio, and they actually have deep and broad range of data all related to immunotherapy of cancer

MOST IMPORTANTLY TSOI has support of key opinion leaders.

Keep up the strong work MR. Timothy DIXON !!
Ashleyspencer
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Re: What's The Future of Cancer Immunotherapy? World Renowned Cancer Expert Shares His Perspective

Post by Ashleyspencer »

Nathan,

I echo your feelings. This is exactly why I bought $TSOI stock

This is a very exciting company. The innovation that the Company had in developing its own "ihub" is so fascinating !!!


Best wishes Professor Dixon !!

Ash
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TimGDixon
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Re: What's The Future of Cancer Immunotherapy? World Renowned Cancer Expert Shares His Perspective

Post by TimGDixon »

You are all so very kind indeed. Yes Franco is incredible - we use to think about cancer in 4 dimensions - Franco changed that to a 5th dimension - that is, the very nature of the "thing". Franco is #2 cited cancer researcher in the world and we are incredibly blessed to have him on our team of other very distinguished scientists and physicians as well. If you listen carefully to his video you will hear him say that big pharma isn't capable of doing what we do - they wouldn't even know where to begin - not really. Their own red-tape prevents it really - i have no red tape except the government and everyone has that red tape so in my humble opinion we are better off for making life changing discoveries long before Roche or Lily or anyone else does.

Welcome aboard!

Tim
curncman
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Donor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipien

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Donor myeloid derived suppressor cells (MDSCs) prolong allogeneic cardiac graft survival through programming of recipient myeloid cells in vivo

https://www.nature.com/articles/s41598-020-71289-z
curncman
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Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm

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Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448601/
Conclusions
The unique mechanism of action of tagraxofusp-erzs and its recent FDA approval has opened a new era for targeted therapy in patients with BPDCN. In the largest clinical trial experience published, with a median age of 70 years, a 90% ORR with 72% CR/CRc rate was observed among 29 previously untreated patients, with 45% being bridged to SCT. The most important toxicity for clinicians to be aware of is that of CLS, which was generally manageable, found to occur frequently at all grades, and which can be recognized early and mitigated with a multidisciplinary management strategy in most cases. Notably, CLS was fatal in 2/94 (2%) patients available for safety evaluation treated with tagraxofusp-erzs leading to is approval. This novel agent represents the first BPDCN-specific therapy now available in the United States, and is a now a welcome option for consideration for therapy in the frontline or R/R setting in those patients with adequate albumin, renal, hepatic, and cardiopulmonary reserve. Now, 1.5 years after tagraxofusp-erzs as a monotherapy agent has been approved, it will be of high interest to continue investigation of this CD123-directed therapy in rational combinations with other targeted agents, hypomethylating agents, and cytotoxic chemotherapy in patients with BPDCN and other hematologic malignancies that overexpress CD123.
curncman
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Global Cell Therapy Market Stem Cell Therapy Market Size Sales Growth Clinical Trials Insight 2027: US$ 40 Billion Oppor

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Global Cell Therapy Market Stem Cell Therapy Market Size Sales Growth Clinical Trials Insight 2027: US$ 40 Billion Opportunity: Kuick Research

https://www.prnewswire.com/in/news-rele ... 06140.html
curncman
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Plasmacytoid dendritic cells cross-prime naive CD8 T cells by transferring antigen to conventional dendritic cells throu

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Plasmacytoid dendritic cells cross-prime naive CD8 T cells by transferring antigen to conventional dendritic cells through exosomes


Chunmei Fu, View ORCID ProfilePeng Peng, Jakob Loschko, View ORCID Profile Li Feng, Phuong Pham, Weiguo Cui, Kelvin P. Lee, Anne B. Krug, and Aimin Jiang

Significance
Whether and how pDCs cross-prime CD8 T cells in vivo remain controversial despite extensive studies. Using a vaccine model where antigens were only delivered to pDCs, this report demonstrated that pDCs induced cross-priming and durable CD8 T cell immunity in vivo. However, cross-presenting pDCs required cDCs to achieve cross-priming by transferring antigens to cDCs. cDC1s but not cDC2s played a critical role in pDC-mediated cross-priming, despite both subsets acquiring antigens from pDCs similarly. Antigen transfer from pDCs to bystander cDCs was mediated by pDC-derived exosomes (pDCexos), which were generated under various conditions. Importantly, these pDCexos required cDCs to prime CD8 T cells, similarly to cross-presenting pDCs, thus identifying the pDCexo/cDCs pathway as a mechanism for pDCs to achieve cross-priming.

Abstract
Although plasmacytoid dendritic cells (pDCs) have been shown to play a critical role in generating viral immunity and promoting tolerance to suppress antitumor immunity, whether and how pDCs cross-prime CD8 T cells in vivo remain controversial. Using a pDC-targeted vaccine model to deliver antigens specifically to pDCs, we have demonstrated that pDC-targeted vaccination led to strong cross-priming and durable CD8 T cell immunity. Surprisingly, cross-presenting pDCs required conventional DCs (cDCs) to achieve cross-priming in vivo by transferring antigens to cDCs. Taking advantage of an in vitro system where only pDCs had access to antigens, we further demonstrated that cross-presenting pDCs were unable to efficiently prime CD8 T cells by themselves, but conferred antigen-naive cDCs the capability of cross-priming CD8 T cells by transferring antigens to cDCs. Although both cDC1s and cDC2s exhibited similar efficiency in acquiring antigens from pDCs, cDC1s but not cDC2s were required for cross-priming upon pDC-targeted vaccination, suggesting that cDC1s played a critical role in pDC-mediated cross-priming independent of their function in antigen presentation. Antigen transfer from pDCs to cDCs was mediated by previously unreported pDC-derived exosomes (pDCexos), that were also produced by pDCs under various conditions. Importantly, all these pDCexos primed naive antigen-specific CD8 T cells only in the presence of bystander cDCs, similarly to cross-presenting pDCs, thus identifying pDCexo-mediated antigen transfer to cDCs as a mechanism for pDCs to achieve cross-priming. In summary, our data suggest that pDCs employ a unique mechanism of pDCexo-mediated antigen transfer to cDCs for cross-priming.
curncman
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Human immunology and immunotherapy: main achievements and challenges

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Human immunology and immunotherapy: main achievements and challenges

https://www.nature.com/articles/s41423-020-00530-6

Abstract
The immune system is a fascinating world of cells, soluble factors, interacting cells, and tissues, all of which are interconnected. The highly complex nature of the immune system makes it difficult to view it as a whole, but researchers are now trying to put all the pieces of the puzzle together to obtain a more complete picture. The development of new specialized equipment and immunological techniques, genetic approaches, animal models, and a long list of monoclonal antibodies, among many other factors, are improving our knowledge of this sophisticated system. The different types of cell subsets, soluble factors, membrane molecules, and cell functionalities are some aspects that we are starting to understand, together with their roles in health, aging, and illness. This knowledge is filling many of the gaps, and in some cases, it has led to changes in our previous assumptions; e.g., adaptive immune cells were previously thought to be unique memory cells until trained innate immunity was observed, and several innate immune cells with features similar to those of cytokine-secreting T cells have been discovered. Moreover, we have improved our knowledge not only regarding immune-mediated illnesses and how the immune system works and interacts with other systems and components (such as the microbiome) but also in terms of ways to manipulate this system through immunotherapy. The development of different types of immunotherapies, including vaccines (prophylactic and therapeutic), and the use of pathogens, monoclonal antibodies, recombinant proteins, cytokines, and cellular immunotherapies, are changing the way in which we approach many diseases, especially cancer.

Introduction
The knowledge of human immunology has improved exponentially in recent years, and more advances in the near future are certainly imminent. The immune system is extremely complex, but we are now developing new tools and skills to study it. Several factors have been involved in these advancements, and the most important ones include the development of thousands of different monoclonal antibodies that allow the identification of a large variety of cell subpopulations and the functional analysis of immune cells. These tools, together with new and sophisticated technologies, such as single-cell analysis, imaging techniques, omics (including massive DNA-RNA sequencing, proteomics, and metabolomics data and new tools for processing these data, such as artificial intelligence and machine learning approaches, mathematical modeling, etc.), newly designed animal models (using conventional transgenic/knockout/knock-in mice or new technologies such as CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats–CRISPR-associated protein 9), are increasing our knowledge about how our immune system functions. The study of the interaction between the immune system and other systems, such as the nervous and endocrine systems or the microbiome, in several illnesses has produced interesting results with important clinical applications.

All of these advances can be applied to several immune-mediated pathologies, but overall, the success achieved with some types of immunotherapies in recent years is revealing new ways to explore and manipulate the immune system for our benefit.

Writing a review about human immunology is a significant challenge, but we have attempted to bring together recent knowledge about the immune system, immune-mediated illnesses and types of immunotherapies.

New findings in fundamental immunology
The last two decades have witnessed a major revolution in the field of immunology. The traditional classification of the immune system into two different arms, namely, innate and adaptive components that collaborate to respond to foreign antigens or to perform self-/nonself-discrimination, has become much more complex. The development and application of new technologies have provided new findings and created a new landscape in which the immune system establishes cross talk, not only between immune components but also with commensal microorganisms1,2 and other important systems, such as the endocrine and nervous systems3,4,5. These developments have forced immunologists to reformulate the immunological architecture that confers protection, which has made the study of the immune system especially attractive. Moreover, these advances have led to an increased interest in better understanding, managing, and manipulating the immune response in both health and disease.

Cell subsets
The characterization of new immune cell subsets has been a constant feature in the immunology field. This evolution is clearly reflected in the discovery of an innate counterpart of T lymphocytes, collectively named innate lymphoid cells (ILCs)6, and in the identification of different types of effector CD4 and regulatory T cells7.

Innate lymphoid cells (ILCs)
ILCs are lymphocytes, but in contrast to adaptive immune cells, they can colonize lymphoid and barrier tissue sites during fetal development, do not undergo somatic recombination and do not express antigen-specific receptors8,9. In addition to lymphoid organs, ILCs are enriched in barrier tissues, such as the gastrointestinal tract, airways, and skin10,11. These innate cells have been considered to be tissue-resident cells, but recent studies suggest that ILCs can migrate through the lymphatic system during homeostasis or enter into the circulation upon infection and inflammation6,12. Currently, five different ILCs are defined on the basis of their transcription factor expression, different cytokine production and/or developmental patterns6: natural killer (NK) cells (discussed below), lymphoid tissue inducer cells (LTis) and three subsets of helper-like ILCs (ILC1s, ILC2s, and ILC3s), which are considered to be the innate counterparts of T helper (Th) 1, Th2, and Th17 cells, respectively. The main focus of this review is ILCs.

ILC1s are dependent on the T-box transcription factor T-bet and produce interferon gamma (INF-γ), but they differ in the expression of eomesodermin transcription factor13. ILC1s express CD127 in humans and CD200R in mice, but the natural cytotoxicity receptor NKp46 (also known as NCR1) is expressed in both species14,15.

ILC2s constitute the most homogeneous class of ILCs; they are dependent on GATA3 and RORα, and they produce type 2 cytokines, mainly interleukin 5 (IL-5) and IL-13. ILC2s are involved in immune responses to parasite infection, and in humans, they express chemoattractant receptor-homologous molecule expressed in TH2 cells (CRTH2) and high levels of CD161, whereas most mouse ILC2s express ST2 (a member of the IL-1 receptor family)14,15.

The development and function of ILC3s depend on the transcription factor RORγt. Both human and mouse ILC3s can produce granulocyte macrophage colony-stimulating factor (GM-CSF), IL-17, and/or IL-2216,17. In humans, two major ILC3 subsets can be distinguished on the basis of the expression of the natural cytotoxicity receptor NKp44 (also known as NCR2)14,15. Both types can produce IL-17, but the production of IL-22 is mainly confined to NKp44+ ILC3s.

Extensive research has focused on deciphering the role of ILCs to ensure the maintenance of tissue homeostasis and immune protection11,18. ILCs express particular sets of receptors in a tissue-specific manner, and these allow the detection of host-derived signals (including those from alarmins, neuronal mediators, microbia, and the diet)19. The integration of these endogenous signals is essential for the maintenance of tissue homeostasis, but dysregulation of ILC responses leads to inflammation and disorder12,20. ILC are mainly involved in early protection against viruses and bacteria13,21, but their response to dysregulated local proinflammatory cytokine production in adipose tissues leads to the development of metabolic disorders and obesity20. IL-5 and IL-13 produced by ILC2s induce goblet cell differentiation and the recruitment of eosinophils, basophils, and mast cells22, which are involved in protection against infection by helminths and viruses, but when uncontrolled, these cells drive allergic responses and metabolic disorders. Moreover, the depletion of ILC2s in animal models suggests a role for these cells in atopic dermatitis and asthma23.

ILC3s are abundant in mucosal tissues, and NCR2+ ILC3s have been proven to be essential for regulating the balance between commensal and pathogenic bacteria through the production of IL-2224. In contrast, NCR2− ILC3s can promote colitis in a model of inflammatory bowel disease25. The lack of immunodeficiency in ILC-deficient patients led to the proposal that ILCs are dispensable in the presence of functional T cells and B cells26. However, recent studies support the idea that ILCs cannot be considered to have functions that only duplicate those of the adaptive immune system.

In addition to those showing the essential role of LTi cells in the formation of secondary lymphoid organs during embryogenesis and the postnatal development of intestinal lymphoid clusters, recent studies also provide evidence that subsets of ILCs express multiple factors that modulate the adaptive immune response in health and disease27,28. In particular, ILC2s and ILC3s modulate the T-cell response. Studies in mice suggest that in healthy intestine, ILC3s express major histocompatibility complex (MHC) class II molecules but lack the expression of costimulatory molecules; therefore, they inhibit microbiota-specific T-cell responses, thus preventing intestinal inflammation29. It seems that the interaction between ILC3s and Tfh cells limits IL-4 secretion and the production of IgA by mucosal B cells30.

Studies with murine models have significantly contributed to the classification and understanding of the role of ILCs in the immune system, especially since similarities have been observed between ILCs identified in mice and humans15. However, the differences between these two species present real challenges15,31 because human ILCs have unique attributes that are only now being elucidated, with further work required in this exciting field. The roles of ILCs in immunity and their cross talk with other components of the immune response await further analysis. Detailed coverage of this topic is beyond the scope of this review, and we refer the reader to recent reviews that provide more information on the biology of human32 and mouse33,34 ILCs.

T cells and plasticity
T cells are categorized as Tα/β and Tγ/δ cells, depending on the type of T-cell receptor (TCR) that they express35. Human Tγ/δ cells, similar to their murine counterparts, are a minor population (1–10% of nucleated cells) in peripheral blood, but are especially abundant in barrier tissues such as the epidermis35,36,37.

The three main subsets of T cells carrying α/β receptor are the CD4+T helper cells and CD8+cytotoxic and CD4+ CD25+ regulatory T cells38.

New effector CD4+ helper T-cell subsets (initially classified as Th1 and Th2)39,40 have been recently described, and at least six human Th cell subsets have been identified to date: Th1, Th2, Th17, Tfh, Th9, and Th22 cells38,41. All of these cells recognize foreign peptides presented by class II MHC molecules on antigen-presenting cells (dendritic cells, macrophages, and B lymphocytes).

Th1 cells are required to activate macrophages and cell-mediated immunity to kill intracellular pathogens42, whereas Th2 cells are important in facilitating eosinophils to fight against parasitic helminths and B cells for antibody production and antibody class-switching to generate IgA or IgE43. Th17 cells are required to mobilize neutrophils for the clearance of fungi and extracellular bacteria, and they are also involved in mucosal protection44. Th9 and Th22 cells are also involved in mucosal immunity; Th9 cells protect against parasites45,46, and Th22 cells prevent microbial translocation across epithelial surfaces and promote wound healing47,48. As mentioned in the introduction to ILCs, studies on human Th cells isolated from lymphoid organs and blood samples, along with recent observations on the developmental mechanism of distinct Th cell subsets, have revealed both similarities and differences of human and mouse Th cells41,49,50.

Tfh cells are very important for germinal center reactions, antibody class switching, affinity maturation, and the development of high affinity antibodies and memory B cells51,52. At the surface marker level, Tfh cells are generally characterized by the expression of CXCR5, the chemokine receptor for CXCL13, which is highly expressed on B-cell follicles for expressing inducible T-cell costimulator (ICOS) and programmed death protein 1 (PD-1)53,54, which enable their involvement in the interaction of Tfh cells and B cells55.

The definition of a given T cell lineage is based on its ability to sense different inductive cytokines, to produce particular cytokines or to express a lineage-specifying transcription factor. Th1 cells produce IFN-γ and express T-bet56; Th2 cells are characterized by IL-4, IL-5, and IL-13 production and GATA-3 expression57,58; pTregs, which are induced in the periphery from naïve precursors, produce TGF-β and express Foxp3 (Tr1 cells are IL-10-secreting Tregs that do not express Foxp3)59. Th17 cells produce IL-17A, IL-17F, and IL-22 and express RORγt60,61, and Tfh cells produce IL-4 and IL-21 and express the BCL6 transcription factor. In addition, Th22 cells, which produce IL-22 and express the aryl hydrocarbon receptor (AHR)47,62, and Th9 cells, are characterized by the expression of IL-9 and the transcription factor PU.163. Additional levels of regulation, such as the differential expression of microRNAs, long noncoding RNAs (lncRNAs), and protein stability and function, have been found to control various aspects of Th cell differentiation and effector function64,65.

CD8+ cytotoxic T cells express the dimeric CD8 marker and have specific lytic capacity to target cells through several mechanisms, including the release of cytotoxic granules, secretion of cytokine tumor necrosis factor alpha (TNFa) and interferon gamma, and the induction of cell death through the interactions of Fas and the Fas ligand38,66. Their TCRs are restricted to interactions with peptides presented by class I MHCs.

Regulatory T cells (Tregs) include thymically derived and peripherally induced regulatory T cells (tTregs and pTregs, respectively), and they produce either IL10, TGF-beta, IL-35 or combinations of these proteins67. tTregs express the transcription factor Foxp3 and secrete IL10 and TGF-β; pTregs, which are induced in the periphery from naïve precursors, can also be subdivided into IL-10-induced Tregs [Tr1 cells] (which secrete large amounts of IL-10 and moderate levels of TGFβ), TH3 cells (which produce IL-10 and TGF-β), and TGFβ-induced Tregs [iTregs], which may or may not express Foxp3.

Moreover, new subsets of regulatory T cells have been described. They include follicular regulatory T cells (which express Foxp3 and Bcl-6 and CXCR5), which modulate the function of Tfh cells and fine-tune the germinal center response68,69,70, and a IL-35-dependent regulatory population of cells (referred to as iTr35 cells), which show potent suppressive potential in several mouse disease models71. Other regulatory populations have also been described, including Bregs and CD8+ Tregs, which are the analogous counterparts of Tregs72,73,74.

Recent studies have revealed the capacity of differentiated T cells, particularly Th17 cell and pTreg subsets, to change their phenotype in response to changing contexts75,76,77,78,79. Becattini et al.78 found that human memory CD4 T cells primed in vivo by pathogens (e.g., Candida albicans and Mycobacterium tuberculosis) or vaccines (Tetanus toxoid) are highly heterogeneous, both at the population and clonal levels. With respect to studies on human arthritis, Nistala et al.79 proposed that Th17 cells are recruited to the joint and converted to Th17/1 or Th1 cells in response to local IL-12 levels. This plasticity has also been observed with in vitro assays under conditions that mimic a disease site, namely, low TGF-β and high IL-12 levels79. These results are inconsistent with the original idea of Th lineage stability and provide new possibilities for disease treatment aimed at inducing particular Th subsets to modulate the immune response against pathogens or to control detrimental immunity76,77,80.
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