86 results
Search Results
52. The Human Microbiota and Skin Cancer.
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Woo, Yu Ri, Cho, Sang Hyun, Lee, Jeong Deuk, and Kim, Hei Sung
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SKIN cancer , *HUMAN microbiota , *SKIN diseases , *ATOPIC dermatitis , *T cells - Abstract
Skin cancer is the most common type of cancer in the US with an increasing prevalence worldwide. While ultraviolet (UV) radiation is a well-known risk factor, there is emerging evidence that the microbiota may also contribute. In recent years, the human microbiota has become a topic of great interest, and its association with inflammatory skin diseases (i.e., atopic dermatitis, acne, rosacea) has been explored. Little is known of the role of microbiota in skin cancer, but with the recognized link between microbial dysbiosis and inflammation, and knowledge that microbiota modulates the effect of UV-induced immunosuppression, theories connecting the two have surfaced. In this paper, we provide a comprehensive review of the key literature on human microbiota, especially the skin microbiota, and skin cancer (i.e., non-melanoma skin cancer, melanoma, cutaneous T cell lymphoma). Also, mechanistic perspectives as to how our microbiota influence skin cancer development and treatment are offered. [ABSTRACT FROM AUTHOR]
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- 2022
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53. The Organization of the Pig T-Cell Receptor γ (TRG) Locus Provides Insights into the Evolutionary Patterns of the TRG Genes across Cetartiodactyla.
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Linguiti, Giovanna, Giannico, Francesco, D'Addabbo, Pietro, Pala, Angela, Caputi Jambrenghi, Anna, Ciccarese, Salvatrice, Massari, Serafina, and Antonacci, Rachele
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LOCUS (Genetics) , *T cells , *GENES , *SWINE , *WILD boar - Abstract
The domestic pig (Sus scrofa) is a species representative of the Suina, one of the four suborders within Cetartiodactyla. In this paper, we reported our analysis of the pig TRG locus in comparison with the loci of species representative of the Ruminantia, Tylopoda, and Cetacea suborders. The pig TRG genomic structure reiterates the peculiarity of the organization of Cetartiodactyla loci in TRGC "cassettes", each containing the basic V-J-J-C unit. Eighteen genes arranged in four TRGC cassettes, form the pig TRG locus. All the functional TRG genes were expressed, and the TRGV genes preferentially rearrange with the TRGJ genes within their own cassette, which correlates the diversity of the γ-chain repertoire with the number of cassettes. Among them, the TRGC5, located at the 5′ end of the locus, is the only cassette that retains a marked homology with the corresponding TRGC cassettes of all the analyzed species. The preservation of the TRGC5 cassette for such a long evolutionary time presumes a highly specialized function of its genes, which could be essential for the survival of species. Therefore, the maintenance of this cassette in pigs confirms that it is the most evolutionarily ancient within Cetartiodactyla, and it has undergone a process of duplication to give rise to the other TRGC cassettes in the different artiodactyl species in a lineage-specific manner. [ABSTRACT FROM AUTHOR]
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- 2022
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54. Sensitivity Analysis of Mathematical Model to Study the Effect of T Cells Infusion in Treatment of CLL.
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Anjum, Asad Ur Rehman, Chaudhry, Qasim Ali, and Almatroud, A. Othman
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SENSITIVITY analysis , *T cells , *MATHEMATICAL models , *MATHEMATICAL analysis , *CHRONIC lymphocytic leukemia - Abstract
In this paper, we considered a mathematical model concerned with the treatment of Chronic Lymphocytic Leukemia (CLL) taking into account the effect of superficially infused T cells in this particular type of tumor. The model is described thoroughly by the system of non-linear differential equations explaining the interaction of naïve, infected, cancer and immune cell population. The detailed sensitivity analysis with the application is the major part of this paper. The basic objective is to provide insight to how parameters' behavior varies model results by elaborating the results obtained from the application of sensitivity analysis. The sensitivity of the model was evaluated not only theoretically, but also with the help of a numerical approach, producing graphs providing better imminent of results. We argue that the application of the sensitivity analysis method endows an insight into how and which parameters are of primary significance in controlling the spread of leukemia. [ABSTRACT FROM AUTHOR]
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- 2020
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55. Current Concepts of Psoriasis Immunopathogenesis.
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Vičić, Marijana, Kaštelan, Marija, Brajac, Ines, Sotošek, Vlatka, and Massari, Larisa Prpić
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PSORIASIS , *SKIN diseases , *ATOPIC dermatitis , *DENDRITIC cells , *CYTOKINES , *IMMUNE response , *T cells - Abstract
Psoriasis is a recurrent, chronic, immune-mediated, systemic inflammatory disease of the skin, joints, and other organic systems. After atopic dermatitis, chronic stationary psoriasis is the most common inflammatory skin disease, affecting an average of 2–4% of the world's population. The disease carries a significant burden due to its numerous comorbidities and the major impact on patients' social and emotional aspects of life. According to current knowledge, psoriasis is a multifactorial disease that occurs in genetically predisposed individuals under various environmental factors, which trigger an immune response disorder with a series of complex inflammatory cascades. The disease is initiated and maintained by mutual interaction of the innate and adaptive immune cells, primarily dendritic cells, T lymphocytes, and keratinocytes, whose leading role alternates at different stages of the disease, consisting mainly in the IL-23/Th17 pathway. Inflammatory events result in consequent epidermal and dermal changes and evolution of the characteristic psoriatic phenotype, respectively. This paper aims to present a comprehensive overview of current knowledge on psoriasis genetic and environmental etiological factors, immunopathogenesis, and the leading cellular and cytokine participants in the inflammatory pathways of this disease. [ABSTRACT FROM AUTHOR]
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- 2021
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56. The Microenvironment's Role in Mycosis Fungoides and Sézary Syndrome: From Progression to Therapeutic Implications.
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Pileri, Alessandro, Guglielmo, Alba, Grandi, Vieri, Violetti, Silvia Alberti, Fanoni, Daniele, Fava, Paolo, Agostinelli, Claudio, Berti, Emilio, Quaglino, Pietro, and Pimpinelli, Nicola
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SEZARY syndrome , *T cells , *PATHOGENESIS , *LYMPHOMAS , *MYCOSIS fungoides , *IMMUNE system - Abstract
Background: Mycosis fungoides (MF) and Sezary Syndrome (SS) are the most common cutaneous T-cell lymphomas. It has been hypothesized that the interaction between the immune system, cutaneous cells, and neoplastic elements may play a role in MF/SS pathogenesis and progression. Methods: This paper aims to revise in a narrative way our current knowledge of the microenvironment's role in MF/SS. Results and Conclusions: Literature data support a possible implication of microenvironment cells in MF/SS pathogenesis and progression, opening up new therapeutic avenues. [ABSTRACT FROM AUTHOR]
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- 2021
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57. 'Off-the-Shelf' Immunotherapy: Manufacture of CD8 + T Cells Derived from Hematopoietic Stem Cells.
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Boyd, Nicholas, Cartledge, Kellie, Cao, Huimin, Evtimov, Vera, Pupovac, Aleta, Trounson, Alan, and Boyd, Richard
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HEMATOPOIETIC stem cells , *T cells , *CORD blood , *T cell differentiation , *T cell receptors , *AUTOGRAFTS - Abstract
Cellular immunotherapy is revolutionizing cancer treatment. However, autologous transplants are complex, costly, and limited by the number and quality of T cells that can be isolated from and expanded for re-infusion into each patient. This paper demonstrates a stromal support cell-free in vitro method for the differentiation of T cells from umbilical cord blood hematopoietic stem cells (HSCs). For each single HSC cell input, approximately 5 × 104 T cells were created with an initial five days of HSC expansion and subsequent T cell differentiation over 49 days. When the induced in vitro differentiated T cells were activated by cytokines and anti-CD3/CD28 beads, CD8+ T cell receptor (TCR) γδ+ T cells were preferentially generated and elicited cytotoxic function against ovarian cancer cells in vitro. This process of inducing de novo functional T cells offers a possible strategy to increase T cell yields, simplify manufacturing, and reduce costs with application potential for conversion into chimeric antigen receptor (CAR)-T cells for cancer immunotherapy and for allogeneic transplantation to restore immune competence. [ABSTRACT FROM AUTHOR]
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- 2021
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58. Adipose Tissue Dendritic Cells: Critical Regulators of Obesity-Induced Inflammation and Insulin Resistance.
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Soedono, Shindy and Cho, Kae Won
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ADIPOSE tissues , *INSULIN resistance , *TYPE 2 diabetes , *OBESITY , *DENDRITIC cells , *T cells , *INFLAMMATION - Abstract
Chronic inflammation of the adipose tissue (AT) is a critical component of obesity-induced insulin resistance and type 2 diabetes. Adipose tissue immune cells, including AT macrophages (ATMs), AT dendritic cells (ATDCs), and T cells, are dynamically regulated by obesity and participate in obesity-induced inflammation. Among AT resident immune cells, ATDCs are master immune regulators and engage in crosstalk with various immune cells to initiate and regulate immune responses. However, due to confounding markers and lack of animal models, their exact role and contribution to the initiation and maintenance of AT inflammation and insulin resistance have not been clearly elucidated. This paper reviews the current understanding of ATDCs and their role in obesity-induced AT inflammation. We also provide the potential mechanisms by which ATDCs regulate AT inflammation and insulin resistance in obesity. Finally, this review offers perspectives on ways to better dissect the distinct functions and contributions of ATDCs to obesity. [ABSTRACT FROM AUTHOR]
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- 2021
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59. Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice.
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Negi, Sushmita, Saini, Sheetal, Tandel, Nikunj, Sahu, Kiran, Mishra, Ravi P.N., and Tyagi, Rajeev K.
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INFLAMMATORY bowel diseases , *REGULATORY T cells , *CROHN'S disease , *LABORATORY mice , *ULCERATIVE colitis , *T cells - Abstract
Crohn's disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD) in humans, afflicted in genetically predisposed individuals due to dysregulated immune response directed against constituents of gut flora. The defective immune responses mounted against the regulatory mechanisms amplify and maintain the IBD-induced mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory immunepathways in the gut may contribute to halting the IBD-associated tissue-damaging immune response. Phenotypic and functional characterization of various immune-suppressive T cells (regulatory T cells; Tregs) over the last decade has been used to optimize the procedures for in vitro expansion of these cells for developing therapeutic interventional strategies. In this paper, we review the mechanisms of action and functional importance of Tregs during the pathogenesis of IBD and modulating the disease induced inflammation as well as role of mouse models including humanized mice repopulated with the human immune system (HIS) to study the IBD. "Humanized" mouse models provide new tools to analyze human Treg ontogeny, immunobiology, and therapy and the role of Tregs in developing interventional strategies against IBD. Overall, humanized mouse models replicate the human conditions and prove a viable tool to study molecular functions of human Tregs to harness their therapeutic potential. [ABSTRACT FROM AUTHOR]
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- 2021
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60. A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia.
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Martínez-Rubio, Álvaro, Chulián, Salvador, Blázquez Goñi, Cristina, Ramírez Orellana, Manuel, Pérez Martínez, Antonio, Navarro-Zapata, Alfonso, Ferreras, Cristina, Pérez-García, Victor M., and Rosa, María
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BONE marrow , *LYMPHOBLASTIC leukemia , *ACUTE leukemia , *AUTOMOBILES , *BONE marrow cells , *T cells , *B cells - Abstract
Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated high rates of response in recurrent B-cell Acute Lymphoblastic Leukemia in children and young adults. Despite this success, a fraction of patients' experience relapse after treatment. Relapse is often preceded by recovery of healthy B cells, which suggests loss or dysfunction of CAR T-cells in bone marrow. This site is harder to access, and thus is not monitored as frequently as peripheral blood. Understanding the interplay between B cells, leukemic cells, and CAR T-cells in bone marrow is paramount in ascertaining the causes of lack of response. In this paper, we put forward a mathematical model representing the interaction between constantly renewing B cells, CAR T-cells, and leukemic cells in the bone marrow. Our model accounts for the maturation dynamics of B cells and incorporates effector and memory CAR T-cells. The model provides a plausible description of the dynamics of the various cellular compartments in bone marrow after CAR T infusion. After exploration of the parameter space, we found that the dynamics of CAR T product and disease were independent of the dose injected, initial B-cell load, and leukemia burden. We also show theoretically the importance of CAR T product attributes in determining therapy outcome, and have studied a variety of possible response scenarios, including second dosage schemes. We conclude by setting out ideas for the refinement of the model. [ABSTRACT FROM AUTHOR]
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- 2021
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61. Insight into Bortezomib Focusing on Its Efficacy against P-gp-Positive MDR Leukemia Cells.
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Kyca, Tomáš, Pavlíková, Lucia, Boháčová, Viera, Mišák, Anton, Poturnayová, Alexandra, Breier, Albert, Sulová, Zdena, and Šereš, Mário
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CYCLIN-dependent kinases , *BORTEZOMIB , *GENE transfection , *CELL cycle , *T cells , *LEUKEMIA , *CYCLINS - Abstract
In this paper, we compared the effects of bortezomib on L1210 (S) cells with its effects on P-glycoprotein (P-gp)-positive variant S cells, which expressed P-gp either after selection with vincristine (R cells) or after transfection with a human gene encoding P-gp (T cells). Bortezomib induced the death-related effects in the S, R, and T cells at concentrations not exceeding 10 nM. Bortezomib-induced cell cycle arrest in the G2/M phase was more pronounced in the S cells than in the R or T cells and was related to the expression levels of cyclins, cyclin-dependent kinases, and their inhibitors. We also observed an increase in the level of polyubiquitinated proteins (via K48-linkage) and a decrease in the gene expression of some deubiquitinases after treatment with bortezomib. Resistant cells expressed higher levels of genes encoding 26S proteasome components and the chaperone HSP90, which is involved in 26S proteasome assembly. After 4 h of preincubation, bortezomib induced a more pronounced depression of proteasome activity in S cells than in R or T cells. However, none of these changes alone or in combination sufficiently suppressed the sensitivity of R or T cells to bortezomib, which remained at a level similar to that of S cells. [ABSTRACT FROM AUTHOR]
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- 2021
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62. Data-Driven Mathematical Model of Osteosarcoma.
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Le, Trang, Su, Sumeyye, Kirshtein, Arkadz, Shahriyari, Leili, and Lamoureux, François
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DISEASE progression , *CYTOKINES , *DENDRITIC cells , *OSTEOSARCOMA , *CELL physiology , *IMMUNE system , *MACROPHAGES , *GENE expression profiling , *STATISTICAL models , *T cells - Abstract
Simple Summary: Osteosarcoma is the most common primary bone tumor and has a poor prognosis. Therefore, it is important to understand the mechanism of the development of osteosarcoma to overcome therapy resistance. Several mathematical models have been developed to study the initiation and progression of many cancer types. However, there are currently no mathematical models for the progression of osteosarcoma, to the best of our knowledge. In this work, we develop a data-driven mathematical model to analyze the impact of the immune cell interactions on the growth of osteosarcoma tumors that have distinct immune patterns. Our model provides a foundation for investigating the effect of various treatments on the dynamics of key players in the primary tumor, including immune cells and cytokines, and ultimately the whole tumor. As the immune system has a significant role in tumor progression, in this paper, we develop a data-driven mathematical model to study the interactions between immune cells and the osteosarcoma microenvironment. Osteosarcoma tumors are divided into three clusters based on their relative abundance of immune cells as estimated from their gene expression profiles. We then analyze the tumor progression and effects of the immune system on cancer growth in each cluster. Cluster 3, which had approximately the same number of naive and M2 macrophages, had the slowest tumor growth, and cluster 2, with the highest population of naive macrophages, had the highest cancer population at the steady states. We also found that the fastest growth of cancer occurred when the anti-tumor immune cells and cytokines, including dendritic cells, helper T cells, cytotoxic cells, and IFN- γ , switched from increasing to decreasing, while the dynamics of regulatory T cells switched from decreasing to increasing. Importantly, the most impactful immune parameters on the number of cancer and total cells were the activation and decay rates of the macrophages and regulatory T cells for all clusters. This work presents the first osteosarcoma progression model, which can be later extended to investigate the effectiveness of various osteosarcoma treatments. [ABSTRACT FROM AUTHOR]
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- 2021
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63. Long-Term Antitumor CD8 + T Cell Immunity Induced by Endogenously Engineered Extracellular Vesicles.
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Ferrantelli, Flavia, Manfredi, Francesco, Chiozzini, Chiara, Leone, Patrizia, Giovannelli, Andrea, Olivetta, Eleonora, Federico, Maurizio, Ashihara, Eishi, and Yamayoshi, Asako
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SURVIVAL , *EXOSOMES , *IMMUNIZATION , *ANIMAL experimentation , *DISEASE vectors , *ANTINEOPLASTIC agents , *T cells , *EXTRACELLULAR space , *CANCER vaccines , *MICE - Abstract
Simple Summary: The induction of an effective immune response against tumor cells is of a great benefit in the battle against cancers. We recently characterized a novel, safe, and cost-effective strategy to induce an efficient CD8+ T cell immune response against potentially whatever antigen. This technique is based on in vivo engineering of exosomes/extracellular vesicles (EVs), i.e., nanovesicles constitutively released by all healthy cells. Immunogenic EVs are generated by intramuscular injection of a DNA vector expressing an EV-anchoring protein fused with the antigen of interest. In this paper, we applied our vaccine platform to counteract the growth of tumors expressing antigens of Human Papilloma Virus (HPV). We demonstrated that this method is instrumental in curing mice already developing HPV-related tumors. In addition, cured mice were shown to resist a second tumor cell implantation. These results could be of relevance for a possible translation into the clinic of our technology. We developed an innovative method to induce antigen-specific CD8+ T cytotoxic lymphocyte (CTL) immunity based on in vivo engineering of extracellular vesicles (EVs). This approach employs a DNA vector expressing a mutated HIV-1 Nef protein (Nefmut) deprived of the anti-cellular effects typical of the wild-type isoform, meanwhile showing an unusual efficiency of incorporation into EVs. This function persists even when foreign antigens are fused to its C-terminus. In this way, Nefmut traffics large amounts of antigens fused to it into EVs spontaneously released by the recipient cells. We previously provided evidence that mice injected with a DNA vector expressing the Nefmut/HPV16-E7 fusion protein developed an E7-specific CTL immune response as detected 2 weeks after the second immunization. Here, we extended and optimized the anti-HPV16 CD8+ T cell immune response induced by the endogenously engineered EVs, and evaluated the therapeutic antitumor efficacy over time. We found that the co-injection of DNA vectors expressing Nefmut fused with E6 and E7 generated a stronger anti-HPV16 immune response compared to that observed in mice injected with the single vectors. When HPV16-E6 and -E7 co-expressing tumor cells were implanted before immunization, all mice survived at day 44, whereas no mice injected with either void or Nefmut-expressing vectors survived until day 32 after tumor implantation. A substantial part of immunized mice (7 out of 12) cleared the tumor. When the cured mice were re-challenged with a second tumor cell implantation, none of them developed tumors. Both E6- and E7-specific CD8+ T immunities were still detectable at the end of the observation time. We concluded that the immunity elicited by engineered EVs, besides counteracting and curing already developed tumors, was strong enough to guarantee the resistance to additional tumor attacks. These results can be of relevance for the therapy of both metastatic and relapsing tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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64. Personalized Immunotherapy Treatment Strategies for a Dynamical System of Chronic Myelogenous Leukemia.
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Valle, Paul A., Coria, Luis N., Plata, Corina, Pérez-García, Víctor M., de Pillis, Lisette, Altrock, Philipp, and Rockne, Russell
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COMPUTER simulation , *CHRONIC myeloid leukemia , *MATHEMATICS , *THEORY , *CELL lines , *T cells , *IMMUNOTHERAPY , *CELL death - Abstract
Simple Summary: As computer performance continues to grow at more affordable costs, mathematical modelling and in silico experimentation begin to play a larger role in understanding cancer evolution. The aim of our work is to formulate a control strategy for the Adaptive Cellular Therapy (ACT) that can fully eradicates the Chronic Myelogenous Leukemia (CML) cells population in a mathematical model describing interactions between naive T cells, effector T cells and CML cancer cells in the circulatory blood system. Mathematical analysis and numerical simulations allow us to conclude that it is possible to design a personalized administration protocol for the ACT in the form of a pulse train with asymmetrical waves and a fixed amplitude to achieve complete CML cancer cells eradication. The amplitude of the impulse on which the treatment is applied is given by an arithmetical combination of the parameters of the system with at least a duty cycle of 45 min/day. This paper is devoted to exploring personalized applications of cellular immunotherapy as a control strategy for the treatment of chronic myelogenous leukemia described by a dynamical system of three first-order ordinary differential equations. The latter was achieved by applying both the Localization of Compact Invariant Sets and Lyapunov's stability theory. Combination of these two approaches allows us to establish sufficient conditions on the immunotherapy treatment parameter to ensure the complete eradication of the leukemia cancer cells. These conditions are given in terms of the system parameters and by performing several in silico experimentations, we formulated a protocol for the therapy application that completely eradicates the leukemia cancer cells population for different initial tumour concentrations. The formulated protocol does not dangerously increase the effector T cells population. Further, complete eradication is considered when solutions go below a finite critical value below which cancer cells cannot longer persist; i.e., one cancer cell. Numerical simulations are consistent with our analytical results. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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65. Targeting the Tumor Microenvironment for Improving Therapeutic Effectiveness in Cancer Immunotherapy: Focusing on Immune Checkpoint Inhibitors and Combination Therapies.
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Chyuan, I-Tsu, Chu, Ching-Liang, Hsu, Ping-Ning, and Bensussan, Armand
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TUMOR treatment , *IMMUNE checkpoint inhibitors , *COMBINATION drug therapy , *CELL physiology , *TREATMENT effectiveness , *T cells , *IMMUNOTHERAPY , *MEDICAL research , *DRUG resistance in cancer cells , *THERAPEUTICS - Abstract
Simple Summary: Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy, and it has greatly expanded our knowledge of anticancer immunity and has introduced breakthroughs in cancer therapy. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. This review provides an overview of recent advances in cellular and molecular factors within the tumor microenvironment (TME) to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies for cancer immunotherapy. The in-depth exploration of complexity within the TME allows for the improvement of therapeutic efficacy and highlights its contribution to cancer immunotherapy. Immune checkpoints play critical roles in the regulation of T-cell effector function, and the effectiveness of their inhibitors in cancer therapy has been established. Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy in general and cancer immunotherapy in particular. Immunotherapy has been indicated to reinvigorate antitumor T-cell activity and dynamically modulate anticancer immune responses. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. Overall, immunotherapy involves a certain degree of uncertainty and complexity. Research on the exploration of cellular and molecular factors within the tumor microenvironment (TME) aims to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies involving the specific targeting of the TME for cancer immunotherapy. The combination of this approach with other types of treatment, including immune checkpoint blockade therapy involving multiple agents, most of the responses and effects in cancer therapy could be significantly enhanced, but the appropriate combinations have yet to be established. Moreover, the in-depth exploration of complexity within the TME allows for the exploration of pathways of immune dysfunction. It may also aid in the identification of new therapeutic targets. This paper reviews recent advances in the improvement of therapeutic efficacy on the immune context of the TME and highlights its contribution to cancer immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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66. The Role of Myeloid-Derived Suppressor Cells (MDSCs) in the Development and/or Progression of Endometriosis-State of the Art.
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Suszczyk, Dorota, Skiba, Wiktoria, Jakubowicz-Gil, Joanna, Kotarski, Jan, Wertel, Iwona, and Götte, Martin
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ENDOMETRIOSIS , *MYELOID-derived suppressor cells , *KILLER cells , *CELL populations , *IMMUNE system , *T cells - Abstract
Endometriosis (EMS) is a common gynecological disease characterized by the presence of endometrial tissue outside the uterus. Approximately 10% of women around the world suffer from this disease. Recent studies suggest that endometriosis has potential to transform into endometriosis-associated ovarian cancer (EAOC). Endometriosis is connected with chronic inflammation and changes in the phenotype, activity, and function of immune cells. The underlying mechanisms include quantitative and functional disturbances of neutrophils, monocytes/macrophages (MO/MA), natural killer cells (NK), and T cells. A few reports have shown that immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) may promote the progression of endometriosis. MDSCs are a heterogeneous population of immature myeloid cells (dendritic cells, granulocytes, and MO/MA precursors), which play an important role in the development of immunological diseases such as chronic inflammation and cancer. The presence of MDSCs in pathological conditions correlates with immunosuppression, angiogenesis, or release of growth factors and cytokines, which promote progression of these diseases. In this paper, we review the impact of MDSCs on different populations of immune cells, focusing on their immunosuppressive role in the immune system, which may be related with the pathogenesis and/or progression of endometriosis and its transformation into ovarian cancer. [ABSTRACT FROM AUTHOR]
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- 2021
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67. Engineering Metabolism of Chimeric Antigen Receptor (CAR) Cells for Developing Efficient Immunotherapies.
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Mangal, Joslyn L., Handlos, Jamie L., Esrafili, Arezoo, Inamdar, Sahil, Mcmillian, Sidnee, Wankhede, Mamta, Gottardi, Riccardo, Acharya, Abhinav P., and Golubovskaya, Vita
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IMMUNE checkpoint inhibitors , *CELL receptors , *MACROPHAGES , *MEDICAL technology , *BIOMEDICAL engineering , *GENE expression , *T cells , *IMMUNOTHERAPY - Abstract
Simple Summary: This review paper here describes the recent progress that has been made in chimeric antigen receptor (CAR) -based therapies for treatment of tumors and the role of metabolism in the tumor microenvironment in relation to these therapies. Moreover, this manuscript also discusses role of different CAR-based cells for treatment of solid tumors, which is a major challenge in the CAR immunotherapy field. Chimeric antigen receptor (CAR) T cell-based therapies have shown tremendous advancement in clinical and pre-clinical studies for the treatment of hematological malignancies, such as the refractory of pre-B cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), and large B cell lymphoma (LBCL). However, CAR T cell therapy for solid tumors has not been successful clinically. Although, some research efforts, such as combining CARs with immune checkpoint inhibitor-based therapy, have been used to expand the application of CAR T cells for the treatment of solid tumors. Importantly, further understanding of the coordination of nutrient and energy supplies needed for CAR T cell expansion and function, especially in the tumor microenvironment (TME), is greatly needed. In addition to CAR T cells, there is great interest in utilizing other types of CAR immune cells, such as CAR NK and CAR macrophages that can infiltrate solid tumors. However, the metabolic competition in the TME between cancer cells and immune cells remains a challenge. Bioengineering technologies, such as metabolic engineering, can make a substantial contribution when developing CAR cells to have an ability to overcome nutrient-paucity in the solid TME. This review introduces technologies that have been used to generate metabolically fit CAR-immune cells as a treatment for hematological malignancies and solid tumors, and briefly discusses the challenges to treat solid tumors with CAR-immune cells. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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68. Adrenergic Signaling in Immunotherapy of Cancer: Friend or Foe?
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Jensen, Agnete Witness Praest, Carnaz Simões, Ana Micaela, thor Straten, Per, Holmen Olofsson, Gitte, and Baxevanis, Constantin N.
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TUMOR treatment , *ADRENERGIC receptors , *CELLULAR signal transduction , *EXERCISE , *IMMUNOTHERAPY , *KILLER cells , *T cells , *PHYSICAL activity - Abstract
Simple Summary: Exercise is associated with many aspects of a healthy lifestyle. Among these, exercise leads to the secretion of adrenaline and noradrenaline, which mobilize cells of the immune system, a process which is suggested to possess therapeutic value in cancer therapy, alone or in combination with immunotherapy. Strikingly, administration of β-blockers—which block the effect of adrenaline/noradrenaline—are also suggested to be useful in cancer therapy alone or in combination with immunotherapy. Herein we discuss the question of whether exercise and the administration of β-blockers could potentially be useful in cancer therapy. The incidence of cancer is increasing worldwide, which is to a large extent related to the population's increasing lifespan. However, lifestyle changes in the Western world are causative as well. Exercise is intrinsically associated with what one could call a "healthy life", and physical activity is associated with a lower risk of various types of cancer. Mouse models of exercise have shown therapeutic efficacy across numerous cancer models, at least in part due to the secretion of adrenaline, which mobilizes cells of the immune system, i.e., cytotoxic T and natural killer (NK) cells, through signaling of the β-2 adrenergic receptor (β2AR). Clinical trials aiming to investigate the clinical value of exercise are ongoing. Strikingly, however, the use of β-blockers—antagonists of the very same signaling pathway—also shows signs of clinical potential in cancer therapy. Cancer cells also express β-adrenergic receptors (βARs) and signaling of the receptor is oncogenic. Moreover, there are data to suggest that β2AR signaling in T cells renders the cell functionally suppressed. In this paper, we discuss these seemingly opposing mechanisms of cancer therapy—exercise, which leads to increased β2AR signaling, and β-blocker treatment, which antagonizes that same signaling—and suggest potential mechanisms and possibilities for their combination. [ABSTRACT FROM AUTHOR]
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- 2021
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69. Peptide Blocking CTLA-4 and B7-1 Interaction.
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Podlesnykh, Stepan V., Abramova, Kristina E., Gordeeva, Anastasia, Khlebnikov, Andrei I., and Chapoval, Andrei I.
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PROGRAMMED cell death 1 receptors , *CYTOTOXIC T lymphocyte-associated molecule-4 , *IMMUNE checkpoint inhibitors , *T cells , *MONOCLONAL antibodies - Abstract
Discovery of the B7 family immune checkpoints such as CTLA-4 (CD152), PD-1 (CD279), as well as their ligands B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), and B7-DC (PD-L2, CD273), has opened new possibilities for cancer immunotherapy using monoclonal antibodies (mAb). The blockade of inhibitory receptors (CTLA-4 and PD-1) with specific mAb results in the activation of cancer patients' T lymphocytes and tumor rejection. However, the use of mAb in clinics has several limitations including side effects and cost of treatment. The development of new low-molecular compounds that block immune checkpoints' functional activity can help to overcome some of these limitations. In this paper, we describe a synthetic peptide (p344) containing 14 amino acids that specifically interact with CTLA-4 protein. A 3D computer model suggests that this peptide binds to the 99MYPPPY104 loop of CTLA-4 protein and potentially blocks the contact of CTLA-4 receptor with B7-1 ligand. Experimental data confirm the peptide-specific interaction with CTLA-4 and its ability to partially block CTLA-4/B7-1 binding. The identified synthetic peptide can be used for the development of novel immune checkpoint inhibitors that can block CTLA-4 functional activity for cancer immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
70. Allogeneic Stem Cell Transplantation in Mantle Cell Lymphoma in the Era of New Drugs and CAR-T Cell Therapy.
- Author
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Marangon, Miriam, Visco, Carlo, Barbui, Anna Maria, Chiappella, Annalisa, Fabbri, Alberto, Ferrero, Simone, Galimberti, Sara, Luminari, Stefano, Musuraca, Gerardo, Re, Alessandro, Zilioli, Vittorio Ruggero, and Ladetto, Marco
- Subjects
- *
LYMPHOMA treatment , *CELL receptors , *HEMATOPOIETIC stem cell transplantation , *T cells - Abstract
Simple Summary: Mantle Cell Lymphoma (MCL) is a lymphoproliferative disorder which represents less than 10% of all non-Hodgkin Lymphomas. The typical course of MCL is characterized by several relapses ("remitting-relapsing" course), and since its identification it has been considered an incurable disease. Allogeneic stem cell transplantation (allo-SCT) has represented in the past years the only treatment which could ensure prolonged remissions, at least in younger patients. In our paper, we critically revised the available data on the use of allo-SCT in MCL. The aim of our review is to identify the subgroups of patients who could best benefit from this therapeutic strategy, the optimal timing for transplantation and the best ways to bridge patients to allo-SCT, in an era in which many novel agents have been developed. MCL is an uncommon lymphoproliferative disorder that has been regarded as incurable since its identification as a distinct entity. Allogeneic transplantation for two decades has represented the only option capable of ensuring prolonged remissions and possibly cure. Despite its efficacy, its application has been limited by feasibility limitations and substantial toxicity, particularly in elderly patients. Nevertheless, the experience accumulated over time has been wide though often scattered among retrospective and small prospective studies. In this review, we aimed at critically revise and discuss available evidence on allogeneic transplantation in MCL, trying to put available evidence into the 2020 perspective, characterized by unprecedented development of novel promising therapeutic agents and regimens. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
71. Immunocyte Membrane-Coated Nanoparticles for Cancer Immunotherapy.
- Author
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Gong, Ping, Wang, Yifan, Zhang, Pengfei, Yang, Zhaogang, Deng, Weiye, Sun, Zhihong, Yang, Mingming, Li, Xuefeng, Ma, Gongcheng, Deng, Guanjun, Dong, Shiyan, Cai, Lintao, and Jiang, Wen
- Subjects
- *
TUMOR treatment , *KILLER cells , *MACROPHAGES , *T cells , *NANOPARTICLES , *IMMUNOTHERAPY - Abstract
Simple Summary: Cancer immunotherapy is a breakthrough in cancer treatment. Unfortunately, despite the encouraging results in clinical treatment, cancer immunotherapy such as CAR-T, PD-1 still faces lots of challenges. Therefore, it is necessary to develop new methods to improve the effectiveness and safety of tumor immunotherapy. In recent years, cell membrane-coated nanomaterial is one of the most promising drug delivery systems and is receiving a great deal of attention due to its naturally biocompatible characteristics. This review summarizes the latest research progress, the advantages, the disadvantages, and the application of immunocyte membrane-coated nanoparticles in cancer immunotherapy. Despite the advances in surface bioconjugation of synthetic nanoparticles for targeted drug delivery, simple biological functionalization is still insufficient to replicate complex intercellular interactions naturally. Therefore, these foreign nanoparticles are inevitably exposed to the immune system, which results in phagocytosis by the reticuloendothelial system and thus, loss of their biological significance. Immunocyte membranes play a key role in intercellular interactions, and can protect foreign nanomaterials as a natural barrier. Therefore, biomimetic nanotechnology based on cell membranes has developed rapidly in recent years. This paper summarizes the development of immunocyte membrane-coated nanoparticles in the immunotherapy of tumors. We will introduce several immunocyte membrane-coated nanocarriers and review the challenges to their large-scale preparation and application. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
72. Dectin-1 and TIM3 Expression in Deep Vein Thrombosis of Lower Limbs (DVTLL).
- Author
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Barresi, Vincenza, Napoli, Salvatore, Spampinato, Giorgia, Condorelli, Daniele Filippo, and Signorelli, Salvatore Santo
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VENOUS thrombosis , *LEG , *T cells , *THROMBOEMBOLISM , *NATURAL immunity - Abstract
The pathophysiological mechanisms of venous thromboembolism are venous stasis, endothelial damage, and hypercoagulability, while less attention has been given to the role of both innate and native immunity. In this paper, we investigate the involvement of the activated immune system detected through some indicators such as TIM3 and Dectin-1 expressed by T lymphocytes. TIM3 and Dectin-1, two surface molecules that regulate the fine-tuning of innate and adaptive immune responses, were evaluated in patients affected by deep vein thrombosis of lower limbs (DVTLL). CD3+, CD4+ and CD8+ T lymphocytes obtained from patients affected by DVTLL were analysed using fluorescence-conjugated antibodies for TIM3 and Dectin-1 by an imaging flow cytometer. DVTLL patients showed a higher number of CD4+ and CD8+ T lymphocytes. TIM3 expression in T lymphocytes was very low in both DVTLL patients and controls. On the contrary, an increase in Dectin-1+ cells among CD4+ and CD8+ T lymphocytes from DVTLL patients was observed. Dectin-1 is known to play a role in inflammation and immunity and our result suggests its potential involvement in thrombotic venous disease. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
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73. CD4 and CD8 Lymphocyte Counts as Surrogate Early Markers for Progression in SARS-CoV-2 Pneumonia: A Prospective Study.
- Author
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Calvet, Joan, Gratacós, Jordi, Amengual, María José, Llop, Maria, Navarro, Marta, Moreno, Amàlia, Berenguer-Llergo, Antoni, Serrano, Alejandra, Orellana, Cristóbal, and Cervantes, Manel
- Subjects
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CD4 lymphocyte count , *SARS-CoV-2 , *LYMPHOCYTE subsets , *BIOMARKERS , *T cells - Abstract
Background: COVID-19 pathophysiology and the predictive factors involved are not fully understood, but lymphocytes dysregulation appears to play a role. This paper aims to evaluate lymphocyte subsets in the pathophysiology of COVID-19 and as predictive factors for severe disease. Patient and methods: A prospective cohort study of patients with SARS-CoV-2 bilateral pneumonia recruited at hospital admission. Demographics, medical history, and data regarding SARS-CoV-2 infection were recorded. Patients systematically underwent complete laboratory tests, including parameters related to COVID-19 as well as lymphocyte subsets study at the time of admission. Severe disease criteria were established at admission, and patients were classified on remote follow-up according to disease evolution. Linear regression models were used to assess associations with disease evolution, and Receiver Operating Characteristic (ROC) and the corresponding Area Under the Curve (AUC) were used to evaluate predictive values. Results: Patients with critical COVID-19 showed a decrease in CD3+CD4+ T cells count compared to non-critical (278 (485 IQR) vs. 545 (322 IQR)), a decrease in median CD4+/CD8+ ratio (1.7, (1.7 IQR) vs. 3.1 (2.4 IQR)), and a decrease in median CD4+MFI (21,820 (4491 IQR) vs. 26,259 (3256 IQR)), which persisted after adjustment. CD3+CD8+ T cells count had a high correlation with time to hospital discharge (PC = −0.700 (−0.931, −0.066)). ROC curves for predictive value showed lymphocyte subsets achieving the best performances, specifically CD3+CD4+ T cells (AUC = 0.756), CD4+/CD8+ ratio (AUC = 0.767), and CD4+MFI (AUC = 0.848). Conclusions: A predictive value and treatment considerations for lymphocyte subsets are suggested, especially for CD3CD4+ T cells. Lymphocyte subsets determination at hospital admission is recommended. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
74. Cancer and Immune Checkpoint Inhibitor Treatment in the Era of SARS-CoV-2 Infection.
- Author
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Gambichler, Thilo, Reuther, Judith, Scheel, Christina H., Susok, Laura, Kern, Peter, and Becker, Jürgen C.
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APOPTOSIS , *IMMUNOSUPPRESSION , *IMMUNOTHERAPY , *T cells , *TUMORS , *VIRUS diseases , *IMMUNE checkpoint inhibitors , *COVID-19 , *THERAPEUTICS - Abstract
Simple Summary: The introduction of immune checkpoint inhibitors (ICI) in 2011 revolutionized the management of many solid cancers and hematological malignancies. However, there are concerns regarding the use of ICI in the era of COVID-19. We present currently available information on the pros and cons of using ICI in cancer patients with respect to the risk of acquiring an infection by SARS-CoV2 and mortality from COVID-19. By means of the present paper, clinicians and researchers may update their knowledge on a highly topical clinical question—is the use of ICI in cancer patients with SARS-CoV2 infection harmful with respect to COVID-19 outcome? Whether cancer patients receiving immune checkpoint inhibitors (ICI) are at an increased risk of severe infection and mortality during the corona pandemic is a hotly debated topic that will continue to evolve. Here, we summarize and discuss current studies regarding COVID-19 and anti-cancer treatment with an emphasis on ICI. Importantly, several lines of evidence suggest that patients currently treated with ICI do not display an increased vulnerability to infection with SARS-CoV-2. Data regarding morbidity and mortality associated with COVID-19 in cancer patients receiving ICI are less clear and often conflicting. Although mostly based on experimental data, it is possible that ICI can promote the exacerbated immune response associated with adverse outcome in COVID-19 patients. On the other hand, mounting evidence suggests that ICI might even be useful in the treatment of viral infections by preventing or ameliorating T cell exhaustion. In this context, the right timing of treatment might be essential. Nevertheless, some cancer patients treated with ICI experience autoimmune-related side effects that require the use of immunosuppressive therapies, which in turn may promote a severe course of infection with SARS-CoV-2. Although there is clear evidence that withholding ICI will have more serious consequences, further studies are urgently needed in to better evaluate the effects of ICI in patients with COVID-19 and the use of ICI during the corona pandemic in general. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
75. Radiotherapy-Mediated Immunomodulation and Anti-Tumor Abscopal Effect Combining Immune Checkpoint Blockade.
- Author
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Zhao, Xinrui and Shao, Chunlin
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THERAPEUTIC use of antineoplastic agents , *TUMOR treatment , *CARCINOGENESIS , *CANCER relapse , *CELL physiology , *COMBINED modality therapy , *IMMUNOTHERAPY , *HEALTH outcome assessment , *RADIATION , *RADIOIMMUNOTHERAPY , *T cells , *IMMUNOLOGIC receptors , *IMMUNE checkpoint inhibitors - Abstract
Simple Summary: Combination of radiotherapy and immunotherapy to antagonize tumors is one of hotspot issues currently. Immunotherapy can effectively alleviate the non-lasting effect of radiotherapy and tumor recurrence. Local radiotherapy can mobilize immune cells into tumor microenvironment and make tumors unable to escape from immune supervision. Therefore, the radio-immunotherapy achieves better curative effects on cancer patients. We have reviewed the regulation of multiple immune cells with different functions by radiotherapy, as well as the mechanism research and clinical outcomes combined with immune checkpoint inhibitors for cancer treatment, which provides new insights in the treatment strategies for certain types of cancer patients in clinic. Radiotherapy (RT) is a conventional method for clinical treatment of local tumors, which can induce tumor-specific immune response and cause the shrinkage of primary tumor and distal metastases via mediating tumor infiltration of CD8+ T cells. Ionizing radiation (IR) induced tumor regression outside the radiation field is termed as abscopal effect. However, due to the mobilization of immunosuppressive signals by IR, the activated CD8+T cells are not sufficient to maintain a long-term positive feedback to make the tumors regress completely. Eventually, the "hot" tumors gradually turn to "cold". With the advent of emerging immunotherapy, the combination of immune checkpoint blockade (ICB) and local RT has produced welcome changes in stubborn metastases, especially anti-PD-1/PD-L1 and anti-CTLA-4 which have been approved in clinical cancer treatment. However, the detailed mechanism of the abscopal effect induced by combined therapy is still unclear. Therefore, how to formulate a therapeutic schedule to maximize the efficacy should be took into consideration according to specific circumstance. This paper reviewed the recent research progresses in immunomodulatory effects of local radiotherapy on the tumor microenvironment, as well as the unique advantage for abscopal effect when combined with ICB, with a view to exploring the potential application value of radioimmunotherapy in clinic. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
76. The Landscape of CAR-T Cell Clinical Trials against Solid Tumors—A Comprehensive Overview.
- Author
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Schaft, Niels
- Subjects
- *
CELLULAR therapy , *CLINICAL trials , *IMMUNOTHERAPY , *EVALUATION of medical care , *T cells , *TUMOR antigens , *HEMATOLOGIC malignancies , *IMMUNOLOGIC receptors - Abstract
Simple Summary: Certain immune cells, namely T cells, of cancer patients can be genetically manipulated to express so-called chimeric antigen receptors (CARs), which enables these cells to kill the tumor cells after recognition by the receptor. This therapy is very successful in the treatment of hematologic tumors such as lymphoma or leukemia. However, tumors growing as a solid mass are less susceptible to this kind of treatment. This review summarizes known data of all clinical trials using this therapy against solid tumors that are registered at clinicaltrials.gov. CAR-T cells showed great potential in the treatment of patients with hematologic tumors. However, the clinical efficacy of CAR-T cells against solid tumors lags behind. To obtain a comprehensive overview of the landscape of CAR-T cell clinical trials against this type of cancer, this review summarizes all the 196 studies registered at clinicaltrials.gov. Special focus is on: (1) geographical distribution; (2) targeted organs, tumor entities, and antigens; (3) CAR transfer methods, CAR formats, and extra features introduced into the T cells; and (4) patient pretreatments, injection sites, and safety measurements. Finally, the few data on clinical outcome are reported. The last assessment of clinicaltrials.gov for the data summarized in this paper was on 4 August 2020. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
77. Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials.
- Author
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Kooshkaki, Omid, Derakhshani, Afshin, Hosseinkhani, Negar, Torabi, Mitra, Safaei, Sahar, Brunetti, Oronzo, Racanelli, Vito, Silvestris, Nicola, and Baradaran, Behzad
- Subjects
- *
PROGRAMMED cell death 1 receptors , *IMMUNE checkpoint inhibitors , *CLINICAL trials , *TARGETED drug delivery , *PROGRAMMED death-ligand 1 , *CYTOTOXIC T cells , *CANCER , *T cells - Abstract
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are inhibitory checkpoints that are commonly seen on activated T cells and have been offered as promising targets for the treatment of cancers. Immune checkpoint inhibitors (ICIs)targeting PD-1, including pembrolizumab and nivolumab, and those targeting its ligand PD-L1, including avelumab, atezolizumab, and durvalumab, and two drugs targeting CTLA-4, including ipilimumab and tremelimumab have been approved for the treatment of several cancers and many others are under investigating in advanced trial phases. ICIs increased antitumor T cells' responses and showed a key role in reducing the acquired immune system tolerance which is overexpressed by cancer and tumor microenvironment. However, 50% of patients could not benefit from ICIs monotherapy. To overcome this, a combination of ipilimumab and nivolumab is frequently investigated as an approach to improve oncological outcomes. Despite promising results for the combination of ipilimumab and nivolumab, safety concerns slowed down the development of such strategies. Herein, we review data concerning the clinical activity and the adverse events of ipilimumab and nivolumab combination therapy, assessing ongoing clinical trials to identify clinical outlines that may support combination therapy as an effective treatment. To the best of our knowledge, this paper is one of the first studies to evaluate the efficacy and safety of ipilimumab and nivolumab combination therapy in several cancers. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
78. Photochemical Internalization: Light Paves Way for New Cancer Chemotherapies and Vaccines.
- Author
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Šošić, Lara, Selbo, Pål Kristian, Kotkowska, Zuzanna K., Kündig, Thomas M., Høgset, Anders, and Johansen, Pål
- Subjects
- *
PHOTOTHERAPY , *TUMOR treatment , *ANTIGENS , *ANTINEOPLASTIC agents , *BLEOMYCIN , *CELL lines , *COMBINED modality therapy , *DRUG delivery systems , *MONOCLONAL antibodies , *PHOTOCHEMOTHERAPY , *PHOTOSENSITIZERS , *T cells , *TUMORS , *SYSTEMATIC reviews , *TREATMENT effectiveness , *DISEASE remission - Abstract
Photochemical internalization (PCI) is a further development of photodynamic therapy (PDT). In this report, we describe PCI as a potential tool for cellular internalization of chemotherapeutic agents or antigens and systematically review the ongoing research. Eighteen published papers described the pre-clinical and clinical developments of PCI-mediated delivery of chemotherapeutic agents or antigens. The studies were screened against pre-defined eligibility criteria. Pre-clinical studies suggest that PCI can be effectively used to deliver chemotherapeutic agents to the cytosol of tumor cells and, thereby, improve treatment efficacy. One Phase-I clinical trial has been conducted, and it demonstrated that PCI-mediated bleomycin treatment was safe and identified tolerable doses of the photosensitizer disulfonated tetraphenyl chlorin (TPCS2a). Likewise, PCI was pre-clinically shown to mediate major histocompatibility complex (MHC) class I antigen presentation and generation of tumor-specific cytotoxic CD8+ T-lymphocytes (CTL) and cancer remission. A first clinical Phase I trial with the photosensitizer TPCS2a combined with human papilloma virus antigen (HPV) was recently completed and results are expected in 2020. Hence, photosensitizers and light can be used to mediate cytosolic delivery of endocytosed chemotherapeutics or antigens. While the therapeutic potential in cancer has been clearly demonstrated pre-clinically, further clinical trials are needed to reveal the true translational potential of PCI in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
79. The Role of Nanovaccine in Cross-Presentation of Antigen-Presenting Cells for the Activation of CD8+ T Cell Responses.
- Author
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Kim, Cheol Gyun, Kye, Yoon-Chul, and Yun, Cheol-Heui
- Subjects
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T cells , *ANTIGEN presenting cells , *MAJOR histocompatibility complex , *CYTOTOXIC T cells , *MEMBRANE fusion , *MATERIALS science - Abstract
Explosive growth in nanotechnology has merged with vaccine development in the battle against diseases caused by bacterial or viral infections and malignant tumors. Due to physicochemical characteristics including size, viscosity, density and electrostatic properties, nanomaterials have been applied to various vaccination strategies. Nanovaccines, as they are called, have been the subject of many studies, including review papers from a material science point of view, although a mode of action based on a biological and immunological understanding has yet to emerge. In this review, we discuss nanovaccines in terms of CD8+ T cell responses, which are essential for antiviral and anticancer therapies. We focus mainly on the role and mechanism, with particular attention to the functional aspects, of nanovaccines in inducing cross-presentation, an unconventional type of antigen-presentation that activates CD8+ T cells upon administration of exogenous antigens, in dendritic cells followed by activation of antigen-specific CD8+ T cell responses. Two major intracellular mechanisms that nanovaccines harness for cross-presentation are described; one is endosomal swelling and rupture, and the other is membrane fusion. Both processes eventually allow exogenous vaccine antigens to be exported from phagosomes to the cytosol followed by loading on major histocompatibility complex class I, triggering clonal expansion of CD8+ T cells. Advancement of nanotechnology with an enhanced understanding of how nanovaccines work will contribute to the design of more effective and safer nanovaccines. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
80. Pharmacological Targeting of GLUT1 to Control Autoreactive T Cell Responses.
- Author
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Di Dedda, Carla, Vignali, Debora, Piemonti, Lorenzo, and Monti, Paolo
- Subjects
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T cells , *GLYCOLYSIS , *TYPE 1 diabetes , *PANCREATIC beta cells , *AUTOIMMUNE diseases , *SMALL molecules - Abstract
An increasing body of evidence indicates that bio-energetic metabolism of T cells can be manipulated to control T cell responses. This potentially finds a field of application in the control of the T cell responses in autoimmune diseases, including in type 1 diabetes (T1D). Of the possible metabolic targets, Glut1 gained considerable interest because of its pivotal role in glucose uptake to fuel glycolysis in activated T cells, and the recent development of a novel class of small molecules that act as selective inhibitor of Glut1. We believe we can foresee a possible application of pharmacological Glut1 blockade approach to control autoreactive T cells that destroy insulin producing beta cells. However, Glut1 is expressed in a broad range of cells in the body and off-target and side effect are possible complications. Moreover, the duration of the treatment and the age of patients are critical aspects that need to be addressed to reduce toxicity. In this paper, we will review recent literature to determine whether it is possible to design a pharmacological Glut1 blocking strategy and how to apply this to autoimmunity in T1D. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
81. The Evolving Role of CD8+CD28− Immunosenescent T Cells in Cancer Immunology.
- Author
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Huff, Wei X., Kwon, Jae Hyun, Henriquez, Mario, Fetcko, Kaleigh, and Dey, Mahua
- Subjects
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TELOMERES , *T cells , *CYTOTOXIC T cells , *CANCER cells , *CELLULAR aging , *CYTOKINE receptors - Abstract
Functional, tumor-specific CD8+ cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8+ effector T cell dysfunction. Among the many facets of CD8+ T cell dysfunction that have been recognized—tolerance, anergy, exhaustion, and senescence—CD8+ T cell senescence is incompletely understood. Naïve CD8+ T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8+CD28− senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8+CD28− senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8+ T cells could improve the efficacy of future anti-tumor immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
82. Beta Glucan: Supplement or Drug? From Laboratory to Clinical Trials.
- Author
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Vetvicka, Vaclav, Vannucci, Luca, Sima, Petr, and Richter, Josef
- Subjects
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IMMUNE response , *CLINICAL trials , *RANDOMIZED controlled trials , *IMMUNOGLOBULINS , *T cells - Abstract
Glucans are part of a group of biologically active natural molecules and are steadily gaining strong attention not only as an important food supplement, but also as an immunostimulant and potential drug. This paper represents an up-to-date review of glucans (β-1,3-glucans) and their role in various immune reactions and the treatment of cancer. With more than 80 clinical trials evaluating their biological effects, the question is not if glucans will move from food supplement to widely accepted drug, but how soon. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
83. Advances in Understanding the Immunological Pathways in Psoriasis.
- Author
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Georgescu, Simona-Roxana, Tampa, Mircea, Caruntu, Constantin, Sarbu, Maria-Isabela, Mitran, Cristina-Iulia, Mitran, Madalina-Irina, Matei, Clara, Constantin, Carolina, and Neagu, Monica
- Subjects
- *
SKIN diseases , *PSORIASIS , *KERATINOCYTES , *T cells , *INTERLEUKINS - Abstract
Psoriasis vulgaris is a chronic, immune-mediated, inflammatory, polygenic skin disorder affecting approximately 2% of the population. It has a great impact on quality of life; patients often experience depression, anxiety, stigma as well as suicidal behavior. Even though psoriasis is one of the most studied dermatological conditions, the pathogenesis of the disease is still not completely elucidated. The complex interactions between keratinocytes, dendritic cells, T-lymphocytes, neutrophils and mast cells are responsible for the histopathological changes seen in psoriasis. The pathogenic model leading to the formation of psoriatic plaques has however evolved a lot over the years. There is now enough evidence to support the role of interleukin (IL) -23, IL-17, IL-22, T helper (Th) -17 cells, Th-22 cells, T regulatory cells, transforming growth factor (TGF)-β1 and IL-10 in the pathogenesis of the disease. Moreover, several inflammatory and anti-inflammatory molecules are currently being investigated, some of them showing promising results. The aim of this paper is to look over the most recent advances in the immunological pathways involved in the pathogenesis of psoriasis vulgaris. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
84. Advanced Materials and Devices for the Regulation and Study of NK Cells.
- Author
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Le Saux, Guillaume and Schvartzman, Mark
- Subjects
- *
KILLER cells , *LYMPHOCYTES , *CYTOKINES , *T cells , *BIOMATERIALS - Abstract
Natural Killer (NK) cells are innate lymphocytes that contribute to immune protection by cytosis, cytokine secretion, and regulation of adaptive responses of T cells. NK cells distinguish between healthy and ill cells, and generate a cytotoxic response, being cumulatively regulated by environmental signals delivered through their diverse receptors. Recent advances in biomaterials and device engineering paved the way to numerous artificial microenvironments for cells, which produce synthetic signals identical or similar to those provided by the physiological environment. In this paper, we review recent advances in materials and devices for artificial signaling, which have been applied to regulate NK cells, and systematically study the role of these signals in NK cell function. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
85. Extracellular Electrophysiology in the Prostate Cancer Cell Model PC-3.
- Author
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Cabello, Miguel, Ge, Haobo, Aracil, Carmen, Moschou, Despina, Estrela, Pedro, Manuel Quero, Jose, I. Pascu, Sofia, and R. F. Rocha, Paulo
- Subjects
- *
PROSTATE cancer , *NANOPARTICLES , *CELL proliferation , *ELECTRODES , *T cells - Abstract
Although prostate cancer is one of the most common cancers in the male population, its basic biological function at a cellular level remains to be fully understood. This lack of in depth understanding of its physiology significantly hinders the development of new, targeted and more effective treatment strategies. Whilst electrophysiological studies can provide in depth analysis, the possibility of recording electrical activity in large populations of non-neuronal cells remains a significant challenge, even harder to address in the picoAmpere-range, which is typical of cellular level electrical activities. In this paper, we present the measurement and characterization of electrical activity of populations of prostate cancer cells PC-3, demonstrating for the first time a meaningful electrical pattern. The low noise system used comprises a multi-electrode array (MEA) with circular gold electrodes on silicon oxide substrates. The extracellular capacitive currents present two standard patterns: an asynchronous sporadic pattern and a synchronous quasi-periodic biphasic spike pattern. An amplitude of ±150 pA, a width between 50–300 ms and an inter-spike interval around 0.5 Hz characterize the quasi-periodic spikes. Our experiments using treatment of cells with Gd3⁺, known as an inhibitor for the Ca2⁺ exchanges, suggest that the quasi-periodic signals originate from Ca2⁺ channels. After adding the Gd3⁺ to a population of living PC-3 cells, their electrical activity considerably decreased; once the culture was washed, thus eliminating the Gd3⁺ containing medium and addition of fresh cellular growth medium, the PC-3 cells recovered their normal electrical activity. Cellular viability plots have been carried out, demonstrating that the PC-3 cells remain viable after the use of Gd3⁺, on the timescale of this experiment. Hence, this experimental work suggests that Ca2⁺ is significantly affecting the electrophysiological communication pattern among PC-3 cell populations. Our measuring platform opens up new avenues for real time and highly sensitive investigations of prostate cancer signalling pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
86. Chemokine Receptors and Exercise to Tackle the Inadequacy of T Cell Homing to the Tumor Site.
- Author
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Idorn, Manja and thor Straten, Per
- Subjects
- *
MELANOMA , *HYPOXEMIA , *T cells , *TUMORS , *GENETIC engineering - Abstract
While cancer immune therapy has revolutionized the treatment of metastatic disease across a wide range of cancer diagnoses, a major limiting factor remains with regard to relying on adequate homing of anti-tumor effector cells to the tumor site both prior to and after therapy. Adoptive cell transfer (ACT) of autologous T cells have improved the outlook of patients with metastatic melanoma. Prior to the approval of checkpoint inhibitors, this strategy was the most promising. However, while response rates of up to 50% have been reported, this strategy is still rather crude. Thus, improvements are needed and within reach. A hallmark of the developing tumor is the evasion of immune destruction. Achieved through the recruitment of immune suppressive cell subsets, upregulation of inhibitory receptors and the development of physical and chemical barriers (such as poor vascularization and hypoxia) leaves the microenvironment a hostile destination for anti-tumor T cells. In this paper, we review the emerging strategies of improving the homing of effector T cells (TILs, CARs, TCR engineered T cells, etc.) through genetic engineering with chemokine receptors matching the chemokines of the tumor microenvironment. While this strategy has proven successful in several preclinical models of cancer and the strategy has moved into the first phase I/II clinical trial in humans, most of these studies show a modest (doubling) increase in tumor infiltration of effector cells, which raises the question of whether road blocks must be tackled for efficient homing. We propose a role for physical exercise in modulating the tumor microenvironment and preparing the platform for infiltration of anti-tumor immune cells. In a time of personalized medicine and genetic engineering, this "old tool" may be a way to augment efficacy and the depth of response to immune therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
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