E. Charrier, R. Vernet, F. Schwenter, P. Luy, A. Donda, N. Mach
Dendritic cells (DC) play a major role during the priming phase of anti-tumor immunization, as they are required for an efficient tumor-associated antigens presentation. At least one dendritic cell-based therapy has already been successfully approved by regulators for clinical application in prostate cancer patients. Moreover, DC development is dependent on the granulocyte macrophage colony stimulating factor (GM-CSF), a cytokine that has been successfully used as a potent inducer of anti-tumoral immunity. To better understand the relation between DC and GM-CSF in anti-tumor immunity, we studied the DC function in mice lacking the cytokine receptor common subunit beta (βc-/-) for GM-CSF, IL-3 and IL-5 and immunized with irradiated tumor cells. Such immunization induces a protective, specific tumor immunization in wild-type mice, while βc-/- mice failed to mount an immune response. Upon in vitro stimulation, DC from βc-/- mice (DCβc-/-) are unable to undergo a full maturation level. In vivo experiments show that they lack the ability to prevent tumor growth, in contrast to DCWT. Moreover, matured DCWT rescued immunization in βc-/- mice. DC maturation is dependent on a functional pathway involving GM-CSF signaling through a biologically functional receptor. These findings may contribute to new strategies for efficient anti-tumor immunotherapies.
{"title":"A Functional GM-CSF Receptor on Dendritic Cells Is Required for Efficient Protective Anti-Tumor Immunity","authors":"E. Charrier, R. Vernet, F. Schwenter, P. Luy, A. Donda, N. Mach","doi":"10.3390/immuno1030016","DOIUrl":"https://doi.org/10.3390/immuno1030016","url":null,"abstract":"Dendritic cells (DC) play a major role during the priming phase of anti-tumor immunization, as they are required for an efficient tumor-associated antigens presentation. At least one dendritic cell-based therapy has already been successfully approved by regulators for clinical application in prostate cancer patients. Moreover, DC development is dependent on the granulocyte macrophage colony stimulating factor (GM-CSF), a cytokine that has been successfully used as a potent inducer of anti-tumoral immunity. To better understand the relation between DC and GM-CSF in anti-tumor immunity, we studied the DC function in mice lacking the cytokine receptor common subunit beta (βc-/-) for GM-CSF, IL-3 and IL-5 and immunized with irradiated tumor cells. Such immunization induces a protective, specific tumor immunization in wild-type mice, while βc-/- mice failed to mount an immune response. Upon in vitro stimulation, DC from βc-/- mice (DCβc-/-) are unable to undergo a full maturation level. In vivo experiments show that they lack the ability to prevent tumor growth, in contrast to DCWT. Moreover, matured DCWT rescued immunization in βc-/- mice. DC maturation is dependent on a functional pathway involving GM-CSF signaling through a biologically functional receptor. These findings may contribute to new strategies for efficient anti-tumor immunotherapies.","PeriodicalId":55599,"journal":{"name":"Immuno-Analyse & Biologie Specialisee","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74039271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Discrepancies in lifespan and healthy-life span are predisposing populations to an increasing burden of age-related disease. Accumulating evidence implicates aging of the immune system, termed immunosenescence, in the pathogenesis of multiple age-related diseases. Moreover, immune dysregulation in the elderly increases vulnerability to infection and dampens pathogen-specific immune responses following vaccination. The health challenges manifesting from these age related deficits have been dramatically exemplified by the current SARS-CoV-2 pandemic. Approaches to either attenuate or reverse functional markers of immunosenescence are therefore urgently needed. Recent evidence suggests systemic immunomodulation via non-specific vaccination with live-attenuated vaccines may be a promising avenue to at least reduce aged population vulnerability to viral infection. This short review describes current understanding of immunosenescence, the historical and mechanistic basis of vaccine-mediated immunomodulation, and the outstanding questions and challenges required for broad adoption.
{"title":"Rescuing Immunosenescence via Non-Specific Vaccination","authors":"Alexander I. Mosa","doi":"10.3390/immuno1030015","DOIUrl":"https://doi.org/10.3390/immuno1030015","url":null,"abstract":"Discrepancies in lifespan and healthy-life span are predisposing populations to an increasing burden of age-related disease. Accumulating evidence implicates aging of the immune system, termed immunosenescence, in the pathogenesis of multiple age-related diseases. Moreover, immune dysregulation in the elderly increases vulnerability to infection and dampens pathogen-specific immune responses following vaccination. The health challenges manifesting from these age related deficits have been dramatically exemplified by the current SARS-CoV-2 pandemic. Approaches to either attenuate or reverse functional markers of immunosenescence are therefore urgently needed. Recent evidence suggests systemic immunomodulation via non-specific vaccination with live-attenuated vaccines may be a promising avenue to at least reduce aged population vulnerability to viral infection. This short review describes current understanding of immunosenescence, the historical and mechanistic basis of vaccine-mediated immunomodulation, and the outstanding questions and challenges required for broad adoption.","PeriodicalId":55599,"journal":{"name":"Immuno-Analyse & Biologie Specialisee","volume":"55 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80607148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-21DOI: 10.20944/PREPRINTS202107.0494.V1
Tobias Russell, Hannah Rowe, C. Bridgewood, R. Cuthbert, A. Watad, D. Newton, E. Jones, D. Mcgonagle
Entheseal spinal inflammation and new bone formation with progressive ankylosis may occur in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). This study evaluated whether JAK inhibition with tofacitinib modulated the key SpA associated cytokines, TNF and IL-17A and whether tofacitinib also modulated bone marrow stromal cell-derived mesenchymal stem cells (MSCs) function including osteogenesis since post inflammation new bone formation occurs in these conditions. Methods: Conventional entheseal derived αβ CD4+ and CD8+ T-cells were in-vestigated following anti-CD3/CD28 bead stimulation to determine IL-17A and TNF levels in Tofacitinib treated (1000nM) peri-entheseal bone (PEB) and peripheral blood mononucleated cells (PBMC) following ELISA. Bone marrow stromal cell-derived mesenchymal stem cells (MSCs) colony forming unit (CFU-F) and multilineage potential was evaluated using tofacitinib (dosages ranging between 100, 500, 1000 and 10000nM). Results: Induced IL-17A and TNF cy-tokine production from both entheseal CD4+ T-cells and CD8+ T-cells were effectively inhibited by tofacitinib. Tofacitinib treatment did not impact on CFU-F potential or in vitro chondro- and osteogenesis. However, tofacitinib stimulation increased MSC adipogenic potential with greater Oil Red O stained area. Conclusion: Inducible IL-17A and TNF production by healthy human entheseal CD4+ and CD8+ T-cells was robustly inhibited in vitro by tofacitinib. However, tofa-citinib did not impact on MSC osteogenesis but stimulated in vitro MSC adipogenesis the relevance of which needs further evaluation given the adipocytes are associated with new bone formation in SpA
{"title":"Tofacitinib Blocks Entheseal Lymphocyte Activation and Modulates MSC Adipogenesis but Does Not Directly Affect Chondro- and Osteogenesis","authors":"Tobias Russell, Hannah Rowe, C. Bridgewood, R. Cuthbert, A. Watad, D. Newton, E. Jones, D. Mcgonagle","doi":"10.20944/PREPRINTS202107.0494.V1","DOIUrl":"https://doi.org/10.20944/PREPRINTS202107.0494.V1","url":null,"abstract":"Entheseal spinal inflammation and new bone formation with progressive ankylosis may occur in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). This study evaluated whether JAK inhibition with tofacitinib modulated the key SpA associated cytokines, TNF and IL-17A and whether tofacitinib also modulated bone marrow stromal cell-derived mesenchymal stem cells (MSCs) function including osteogenesis since post inflammation new bone formation occurs in these conditions. Methods: Conventional entheseal derived αβ CD4+ and CD8+ T-cells were in-vestigated following anti-CD3/CD28 bead stimulation to determine IL-17A and TNF levels in Tofacitinib treated (1000nM) peri-entheseal bone (PEB) and peripheral blood mononucleated cells (PBMC) following ELISA. Bone marrow stromal cell-derived mesenchymal stem cells (MSCs) colony forming unit (CFU-F) and multilineage potential was evaluated using tofacitinib (dosages ranging between 100, 500, 1000 and 10000nM). Results: Induced IL-17A and TNF cy-tokine production from both entheseal CD4+ T-cells and CD8+ T-cells were effectively inhibited by tofacitinib. Tofacitinib treatment did not impact on CFU-F potential or in vitro chondro- and osteogenesis. However, tofacitinib stimulation increased MSC adipogenic potential with greater Oil Red O stained area. Conclusion: Inducible IL-17A and TNF production by healthy human entheseal CD4+ and CD8+ T-cells was robustly inhibited in vitro by tofacitinib. However, tofa-citinib did not impact on MSC osteogenesis but stimulated in vitro MSC adipogenesis the relevance of which needs further evaluation given the adipocytes are associated with new bone formation in SpA","PeriodicalId":55599,"journal":{"name":"Immuno-Analyse & Biologie Specialisee","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78890587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The increased prevalence of neurodegenerative diseases, especially during the COVID-19 outbreak, necessitates the search for natural immune- and cognitive-enhancing agents. 10-Hydroxy-trans-2-decenoic acid (10-H2DA), the main fatty acid of royal jelly, has several pharmacological activities. Given the fundamental role of astrocytes in regulating immune responses of the central nervous system, we used cortical astrocytes to examine the effect of 10-H2DA on the expression of genes associated with neuroinflammation and the production of neurotrophins, as well as cellular resistance to H2O2-induced cytotoxicity. Astrocytes, pretreated with a range of concentrations of 10-H2DA for 24 h, were exposed to lipopolysaccharide (LPS) for 3 h, after which the expression of proinflammatory cytokines (IL-1β, IL-6, and tumor necrosis factor-α (TNF-α)) and neurotrophic factors (BDNF, GDNF, and IGF-1) was evaluated. In the absence of LPS, 10-H2DA had no significant effect on the mRNA expression of neurotrophins or cytokines except for IL-1β, which significantly increased with low doses of 10-H2DA (3 µM). 10-H2DA (10 µM) pretreatment of LPS-stimulated cells did not significantly inhibit the expression of cytokine encoding genes; however, it significantly lowered the mRNA expression of GDNF and tended to decrease BDNF and IGF-1 expression compared with LPS alone. Additionally, 10-H2DA did not protect astrocytes against H2O2-induced oxidative stress. Our data indicate no anti-inflammatory, antioxidant, or neurotrophic effect of 10-H2DA in astrocytes undergoing inflammation or oxidative stress. The effect of IGF-1 inhibition by 10-H2DA on neuronal ketogenesis needs investigation.
{"title":"The Effects of Royal Jelly Acid, 10-Hydroxy-trans-2-decenoic Acid, on Neuroinflammation and Oxidative Stress in Astrocytes Stimulated with Lipopolysaccharide and Hydrogen Peroxide","authors":"A. Ali, H. Kunugi","doi":"10.3390/IMMUNO1030013","DOIUrl":"https://doi.org/10.3390/IMMUNO1030013","url":null,"abstract":"The increased prevalence of neurodegenerative diseases, especially during the COVID-19 outbreak, necessitates the search for natural immune- and cognitive-enhancing agents. 10-Hydroxy-trans-2-decenoic acid (10-H2DA), the main fatty acid of royal jelly, has several pharmacological activities. Given the fundamental role of astrocytes in regulating immune responses of the central nervous system, we used cortical astrocytes to examine the effect of 10-H2DA on the expression of genes associated with neuroinflammation and the production of neurotrophins, as well as cellular resistance to H2O2-induced cytotoxicity. Astrocytes, pretreated with a range of concentrations of 10-H2DA for 24 h, were exposed to lipopolysaccharide (LPS) for 3 h, after which the expression of proinflammatory cytokines (IL-1β, IL-6, and tumor necrosis factor-α (TNF-α)) and neurotrophic factors (BDNF, GDNF, and IGF-1) was evaluated. In the absence of LPS, 10-H2DA had no significant effect on the mRNA expression of neurotrophins or cytokines except for IL-1β, which significantly increased with low doses of 10-H2DA (3 µM). 10-H2DA (10 µM) pretreatment of LPS-stimulated cells did not significantly inhibit the expression of cytokine encoding genes; however, it significantly lowered the mRNA expression of GDNF and tended to decrease BDNF and IGF-1 expression compared with LPS alone. Additionally, 10-H2DA did not protect astrocytes against H2O2-induced oxidative stress. Our data indicate no anti-inflammatory, antioxidant, or neurotrophic effect of 10-H2DA in astrocytes undergoing inflammation or oxidative stress. The effect of IGF-1 inhibition by 10-H2DA on neuronal ketogenesis needs investigation.","PeriodicalId":55599,"journal":{"name":"Immuno-Analyse & Biologie Specialisee","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89154014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The past decades of cancer immunotherapy research have provided profound evidence that the immune system is capable of inducing durable tumor regression. Although many commercialized anti-cancer immunotherapies are available to patients, these treatment options only scrape the surface of the potential immune-related treatment possibilities for cancer. Additionally, many individuals are ineligible for established immunotherapies due to their cancer type. The adoptive cell transfer of autologous tumor-infiltrating lymphocytes has been used in humans for over 30 years to treat metastatic melanoma, and continued modifications are making it increasingly more effective against other types of cancer. This comprehensive review outlines this therapy from its infancy through to the present day, bringing to light modifications and optimizations to the traditional workflow, as well as highlighting the influence of new methods and technologies.
{"title":"ACT Up TIL Now: The Evolution of Tumor-Infiltrating Lymphocytes in Adoptive Cell Therapy for the Treatment of Solid Tumors","authors":"T. Hulen, C. Chamberlain, I. Svane, Ö. Met","doi":"10.3390/IMMUNO1030012","DOIUrl":"https://doi.org/10.3390/IMMUNO1030012","url":null,"abstract":"The past decades of cancer immunotherapy research have provided profound evidence that the immune system is capable of inducing durable tumor regression. Although many commercialized anti-cancer immunotherapies are available to patients, these treatment options only scrape the surface of the potential immune-related treatment possibilities for cancer. Additionally, many individuals are ineligible for established immunotherapies due to their cancer type. The adoptive cell transfer of autologous tumor-infiltrating lymphocytes has been used in humans for over 30 years to treat metastatic melanoma, and continued modifications are making it increasingly more effective against other types of cancer. This comprehensive review outlines this therapy from its infancy through to the present day, bringing to light modifications and optimizations to the traditional workflow, as well as highlighting the influence of new methods and technologies.","PeriodicalId":55599,"journal":{"name":"Immuno-Analyse & Biologie Specialisee","volume":"184 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77441907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
NK cells are lymphocytes involved in the innate and adaptative immune response. These cells are located in peripheral blood and tissues with ample functions, from immune vigilant to tolerogenic reactions. In the endometrium, NK cell populations vary depending on age, hormones, and inflammation. When pregnancy occurs, tissue-resident NK cells and conventional NK cells are recruited to protect the fetus, a tolerogenic response. On the contrary, in the inflamed endometrium, various inflammatory cells down-regulate NK tolerance and impair embryo implantation. Therefore, NK cells’ pharmacological modulation is difficult to achieve. Several strategies have been used, from progesterone, lipid emulsions to steroids; the success has not been as expected. However, new therapeutic approaches have been proposed to decrease the endometrial inflammatory burden and increase pregnancy success based on understanding NK cell physiology.
{"title":"A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation","authors":"J. Garmendia, J. D. de Sanctis","doi":"10.3390/IMMUNO1030011","DOIUrl":"https://doi.org/10.3390/IMMUNO1030011","url":null,"abstract":"NK cells are lymphocytes involved in the innate and adaptative immune response. These cells are located in peripheral blood and tissues with ample functions, from immune vigilant to tolerogenic reactions. In the endometrium, NK cell populations vary depending on age, hormones, and inflammation. When pregnancy occurs, tissue-resident NK cells and conventional NK cells are recruited to protect the fetus, a tolerogenic response. On the contrary, in the inflamed endometrium, various inflammatory cells down-regulate NK tolerance and impair embryo implantation. Therefore, NK cells’ pharmacological modulation is difficult to achieve. Several strategies have been used, from progesterone, lipid emulsions to steroids; the success has not been as expected. However, new therapeutic approaches have been proposed to decrease the endometrial inflammatory burden and increase pregnancy success based on understanding NK cell physiology.","PeriodicalId":55599,"journal":{"name":"Immuno-Analyse & Biologie Specialisee","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73092993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-06-28DOI: 10.20944/preprints202106.0666.v1
Y. Komohara, Toshiki Anami, K. Asano, Yukio Fujiwara, Junji Yatsuda, T. Kamba
Lymph nodes are secondary lymphoid organs that appear as bean-like nodules usually <1 cm in size, and they are localized throughout the body. Many antigen-presenting cells such as dendritic cells and macrophages reside in lymph nodes, where they mediate host defense responses against pathogens such as viruses and bacteria. In cancers, antigen-presenting cells induce cytotoxic T lymphocytes (CTLs) to react to cancer cell–derived antigens. Macrophages located in the lymph node sinus are of particular interest in relation to anti-cancer immune responses because many studies using both human specimens and animal models have suggested that lymph node macrophages play a key role in activating anti-cancer CTLs. The regulation of lymph node macrophages therefore represents a potentially promising novel approach in anti-cancer therapy.
{"title":"Anti-cancer Immune Reaction and Lymph Node Macrophage; A Review from Human and Animal Studies","authors":"Y. Komohara, Toshiki Anami, K. Asano, Yukio Fujiwara, Junji Yatsuda, T. Kamba","doi":"10.20944/preprints202106.0666.v1","DOIUrl":"https://doi.org/10.20944/preprints202106.0666.v1","url":null,"abstract":"Lymph nodes are secondary lymphoid organs that appear as bean-like nodules usually <1 cm in size, and they are localized throughout the body. Many antigen-presenting cells such as dendritic cells and macrophages reside in lymph nodes, where they mediate host defense responses against pathogens such as viruses and bacteria. In cancers, antigen-presenting cells induce cytotoxic T lymphocytes (CTLs) to react to cancer cell–derived antigens. Macrophages located in the lymph node sinus are of particular interest in relation to anti-cancer immune responses because many studies using both human specimens and animal models have suggested that lymph node macrophages play a key role in activating anti-cancer CTLs. The regulation of lymph node macrophages therefore represents a potentially promising novel approach in anti-cancer therapy.","PeriodicalId":55599,"journal":{"name":"Immuno-Analyse & Biologie Specialisee","volume":"548 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80191286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Apolline de Folmont, J. Bourhis, S. Chouaib, S. Terry
Evading the immune system is one of the hallmarks of cancer. Tumors escape anti-tumor immunity through cell-intrinsic means and the assembly of an immunosuppressive tumor microenvironment. By significantly boosting the host immune system, cancer immunotherapies targeting immune checkpoint receptors (CTLA-4 and PD-1) improved survival in patients even with cancers previously considered rapidly fatal. Nevertheless, an important group of patients is refractory or relapse rapidly. The factors involved in the heterogeneous responses observed are still poorly understood. Other immunotherapeutic approaches are being developed that may widen the options, including adoptive cell therapy using CAR-T cells alone or in combination. Despite impressive results in B cell malignancies, many caveats and unanswered questions remain in other cancers, thus limiting the potential of this approach to treat aggressive diseases. In particular, a complex TME could impair the survival, proliferation, and effector functions of CAR-T cells. Recent reports highlight the potential of targeting TGF-β signaling to improve CAR-T cell therapy. TGF-β is a well-known regulatory cytokine with pleiotropic effects in the TME, including immunosuppression. This review summarizes recent work investigating the potential effects of TGF-β within the TME, with a focus on CAR-T behavior and efficacy. We also discuss several key questions to be addressed to accelerate clinical translation of this approach.
{"title":"Multifaceted Role of the Transforming Growth Factor β on Effector T Cells and the Implication for CAR-T Cell Therapy","authors":"Apolline de Folmont, J. Bourhis, S. Chouaib, S. Terry","doi":"10.3390/immuno1030010","DOIUrl":"https://doi.org/10.3390/immuno1030010","url":null,"abstract":"Evading the immune system is one of the hallmarks of cancer. Tumors escape anti-tumor immunity through cell-intrinsic means and the assembly of an immunosuppressive tumor microenvironment. By significantly boosting the host immune system, cancer immunotherapies targeting immune checkpoint receptors (CTLA-4 and PD-1) improved survival in patients even with cancers previously considered rapidly fatal. Nevertheless, an important group of patients is refractory or relapse rapidly. The factors involved in the heterogeneous responses observed are still poorly understood. Other immunotherapeutic approaches are being developed that may widen the options, including adoptive cell therapy using CAR-T cells alone or in combination. Despite impressive results in B cell malignancies, many caveats and unanswered questions remain in other cancers, thus limiting the potential of this approach to treat aggressive diseases. In particular, a complex TME could impair the survival, proliferation, and effector functions of CAR-T cells. Recent reports highlight the potential of targeting TGF-β signaling to improve CAR-T cell therapy. TGF-β is a well-known regulatory cytokine with pleiotropic effects in the TME, including immunosuppression. This review summarizes recent work investigating the potential effects of TGF-β within the TME, with a focus on CAR-T behavior and efficacy. We also discuss several key questions to be addressed to accelerate clinical translation of this approach.","PeriodicalId":55599,"journal":{"name":"Immuno-Analyse & Biologie Specialisee","volume":"139 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75028183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Age-induced cellular senescence leads to a decline in efficacy of immune response and an increase in morbidity and mortality. Physical activity may be an intervention to slow down or reverse this process for elderly individuals or even delay it via enhanced activity over their lifespan. The aim of this systematic review was to analyze and discuss the current evidence of the effects of physical activity on senescence in leukocyte subpopulations. Two electronic databases (PubMed, Web of Science) were scanned in July 2020. Studies performing endurance or resistance exercise programs and investigating leukocytes of healthy, particularly elderly subjects were included. Nine human studies were identified, including a total of 440 participants, of which two studies examined different types of exercise training retrospectively, three conducted resistance exercise, three endurance exercise, and one endurance vs. resistance training. Results revealed that exercise training increased the naïve subsets of peripheral T-helper cells and cytotoxic T-cells, whereas the senescent and effector memory T-cells re-expresses CD45RA (TEMRA) subsets decreased. Moreover, the percentage of T-helper- compared to cytotoxic T-cells increased. The results suggest that physical activity reduces or slows down cellular immunosenescence. Endurance exercise seems to affect cellular senescence in a more positive way than resistance training. However, training contents and sex also influence senescent cells. Explicit mechanisms need to be clarified.
年龄诱导的细胞衰老导致免疫应答效能下降，发病率和死亡率增加。对于老年人来说，体育活动可能是一种干预措施，可以减缓或逆转这一过程，甚至可以通过在他们的一生中增加活动来延缓这一过程。本系统综述的目的是分析和讨论体力活动对白细胞亚群衰老影响的现有证据。2020年7月对两个电子数据库(PubMed, Web of Science)进行了扫描。包括进行耐力或阻力运动项目的研究，以及调查健康人，特别是老年人的白细胞。我们确定了9项人体研究，包括440名参与者，其中2项研究回顾了不同类型的运动训练，3项进行了阻力训练，3项进行了耐力训练，1项进行了耐力与阻力训练。结果显示，运动训练增加了外周t辅助细胞和细胞毒性t细胞的naïve亚群，而衰老和效应记忆t细胞重新表达CD45RA (TEMRA)亚群减少。此外，与细胞毒性t细胞相比，辅助t细胞的百分比增加了。结果表明，体育活动可以减少或减缓细胞免疫衰老。耐力运动似乎比抗阻训练更积极地影响细胞衰老。然而，训练内容和性别也会影响细胞的衰老。明确的机制需要澄清。
{"title":"The Effects of Physical Activity on the Aging of Circulating Immune Cells in Humans: A Systematic Review","authors":"Lara Brauer, K. Krüger, C. Weyh, K. Alack","doi":"10.3390/immuno1030009","DOIUrl":"https://doi.org/10.3390/immuno1030009","url":null,"abstract":"Age-induced cellular senescence leads to a decline in efficacy of immune response and an increase in morbidity and mortality. Physical activity may be an intervention to slow down or reverse this process for elderly individuals or even delay it via enhanced activity over their lifespan. The aim of this systematic review was to analyze and discuss the current evidence of the effects of physical activity on senescence in leukocyte subpopulations. Two electronic databases (PubMed, Web of Science) were scanned in July 2020. Studies performing endurance or resistance exercise programs and investigating leukocytes of healthy, particularly elderly subjects were included. Nine human studies were identified, including a total of 440 participants, of which two studies examined different types of exercise training retrospectively, three conducted resistance exercise, three endurance exercise, and one endurance vs. resistance training. Results revealed that exercise training increased the naïve subsets of peripheral T-helper cells and cytotoxic T-cells, whereas the senescent and effector memory T-cells re-expresses CD45RA (TEMRA) subsets decreased. Moreover, the percentage of T-helper- compared to cytotoxic T-cells increased. The results suggest that physical activity reduces or slows down cellular immunosenescence. Endurance exercise seems to affect cellular senescence in a more positive way than resistance training. However, training contents and sex also influence senescent cells. Explicit mechanisms need to be clarified.","PeriodicalId":55599,"journal":{"name":"Immuno-Analyse & Biologie Specialisee","volume":"63 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73887309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The development of tumors requires an initiator event, usually exposure to DNA damaging agents that cause genetic alterations such as gene mutations or chromosomal abnormalities, leading to deregulated cell proliferation. Although the mere stochastic accumulation of further mutations may cause tumor progression, it is now clear that an inflammatory microenvironment has a major tumor-promoting influence on initiated cells, in particular when a chronic inflammatory reaction already existed before the initiated tumor cell was formed. Moreover, inflammatory cells become mobilized in response to signals emanating from tumor cells. In both cases, the microenvironment provides signals that initiated tumor cells perceive by membrane receptors and transduce via downstream kinase cascades to modulate multiple cellular processes and respond with changes in cell gene expression, metabolism, and morphology. Cytokines, chemokines, and growth factors are examples of major signals secreted by immune cells, fibroblast, and endothelial cells and mediate an intricate cell-cell crosstalk in an inflammatory microenvironment, which contributes to increased cancer cell survival, phenotypic plasticity and adaptation to surrounding tissue conditions. Eventually, consequent changes in extracellular matrix stiffness and architecture, coupled with additional genetic alterations, further fortify the malignant progression of tumor cells, priming them for invasion and metastasis. Here, we provide an overview of the current knowledge on the composition of the inflammatory tumor microenvironment, with an emphasis on the major signals and signal-transducing events mediating different aspects of stromal cell-tumor cell communication that ultimately lead to malignant progression.
{"title":"A Signaling View into the Inflammatory Tumor Microenvironment","authors":"Joana F. S. Pereira, P. Jordan, P. Matos","doi":"10.3390/IMMUNO1020007","DOIUrl":"https://doi.org/10.3390/IMMUNO1020007","url":null,"abstract":"The development of tumors requires an initiator event, usually exposure to DNA damaging agents that cause genetic alterations such as gene mutations or chromosomal abnormalities, leading to deregulated cell proliferation. Although the mere stochastic accumulation of further mutations may cause tumor progression, it is now clear that an inflammatory microenvironment has a major tumor-promoting influence on initiated cells, in particular when a chronic inflammatory reaction already existed before the initiated tumor cell was formed. Moreover, inflammatory cells become mobilized in response to signals emanating from tumor cells. In both cases, the microenvironment provides signals that initiated tumor cells perceive by membrane receptors and transduce via downstream kinase cascades to modulate multiple cellular processes and respond with changes in cell gene expression, metabolism, and morphology. Cytokines, chemokines, and growth factors are examples of major signals secreted by immune cells, fibroblast, and endothelial cells and mediate an intricate cell-cell crosstalk in an inflammatory microenvironment, which contributes to increased cancer cell survival, phenotypic plasticity and adaptation to surrounding tissue conditions. Eventually, consequent changes in extracellular matrix stiffness and architecture, coupled with additional genetic alterations, further fortify the malignant progression of tumor cells, priming them for invasion and metastasis. Here, we provide an overview of the current knowledge on the composition of the inflammatory tumor microenvironment, with an emphasis on the major signals and signal-transducing events mediating different aspects of stromal cell-tumor cell communication that ultimately lead to malignant progression.","PeriodicalId":55599,"journal":{"name":"Immuno-Analyse & Biologie Specialisee","volume":"212 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74633079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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