Fatal neuroendocrine prostate cancer (NEPC) often emerges in patients relapsing after hormone the... more Fatal neuroendocrine prostate cancer (NEPC) often emerges in patients relapsing after hormone therapies. Besides, de novo NEPC can rarely occur in treatment-naïve patients. Treatment-related and de-novo NEPC have different genomic alterations but share a common transcriptional profile. Investigating the tumor microenvironment, we recently found that mast cells (MCs) accumulate within hormone-sensitive prostate cancer favoring its growth, whereas are excluded by de-novo NEPC both in patients and in the transgenic TRAMP spontaneous mouse model. TRAMP mice backcrossed with MCs-deficient KitWsh mice showed increased frequency of de-novo NEPC. The frequency of de-novo NEPC similarly raised also in TRAMP mice deficient for the matricellular protein osteopontin (OPN). Reconstituting KitWsh-TRAMP mice with wild type, but not with OPN-deficient, MCs lowered the frequency of NEPC to that of untreated TRAMP mice. We found that MCs stain positive for OPN in tumor sections and in vitro cultures, but release a tiny amount of OPN in supernatants if compared to NEPC cells. Notably, OPN has both secreted (sOPN) and intracellular (iOPN) forms; the latter can bind to MyD88 and regulate the signaling downstream toll-like receptors (TLRs). In vitro, wild type, but not OPN-/- or MyD88-/-, MCs inhibited the proliferation of NEPC cells. Also, in silico analyses showed that genes related to inflammatory response and TLRs signaling are down regulated in human and murine NEPC.Our data suggest that TLRs/MyD88/iOPN-mediated pathways induce MCs to release factor(s) able to restrain NEPC. Further studies are required to molecularly dissect this novel function of MCs, to identify actionable targets against NEPC. Citation Format: Roberta Sulsenti, Barbara Frossi, Valeria Cancila, Claudia Enriquez, Renata Ferri, Sabina Sangaletti, Claudio Tripodo, Carlo Emilio Pucillo, Mario Paolo Colombo, Elena Jachetti. The protective role of mast cells against neuroendocrine prostate cancer depends on the release of cytokines mediated by intracellular osteopontin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2556.
Supplementary Figure 1. Representative plots illustrating analysis of tumor-specific CD8+ T cell ... more Supplementary Figure 1. Representative plots illustrating analysis of tumor-specific CD8+ T cell response in TRAMP and KitWsh-TRAMP mice. Supplementary Figure 2. CD8+T cells from PDLN and prostates of KitWsh-TRAMP mice are responsive. Supplementary Figure 3. Quantification of MCs or T cells after reconstitution of depletion, respectively. Supplementary Figure 4. Flow cytometry identification of T cells in spleen and prostate of TRAMP and KitWsh-TRAMP mice. Supplementary Figure 5. Flow cytometry identification of myeloid cells in spleen and prostate of TRAMP and KitWsh-TRAMP mice. Supplementary Figure 6. MCs and PMN-MDSC can interact via CD40L-CD40 in TRAMP mice. Supplementary Figure 7. Wild type and CD40L-/- BMMC are equally functional, but CD8+T cells from PDLN and prostates of KitWsh-TRAMP mice reconstituted with BMMC CD40L-/- are still responsive. Supplementary Figure 8. MCs, CD40L and CD33 co-localize in human tumor prostate cancer samples. Supplementary Figure 9. Correlation between MC-genes and MDSC-activity genes in human prostate cancer data sets. Supplementary Figure 10. MC/PMN-MDSC signatures outperform random signatures of the same length.
OX40L is expressed by many cell types, including antigen presenting cells (APCs), T cells, vascul... more OX40L is expressed by many cell types, including antigen presenting cells (APCs), T cells, vascular endothelial cells, mast cells (MCs), and natural killer cells. The importance of OX40L:OX40 interactions and the OX40L signaling is crucial for the homeostasis and for the modulation of the effector functions of the immune system. However, the lack of non-murine/non-IgG commercially available OX40L-triggering antibodies and the potential signal cross-contamination caused by the binding to the FcγRs co-expressed by several immune cells have limited the study of the OX40L-signaling cascade. We recently characterized the functions and described the molecular events, which follow the engagement of OX40L in MCs, by the use of the soluble OX40 molecule, able to mimic the regulatory T cell-driven engagement of MC-OX40L. This molecule enables signaling studies in MCs with any requirement for OX40-expressing cells. Using this unique reagent, we determined the modality and the extent by which the engagement of OX40L in MCs influences the IgE-dependent MC degranulation. This tool may find a potential application for signaling studies of other OX40L-expressing populations other than MCs, mainly APCs, with similar approaches we reported for the study of OX40L cascade.
Allergic rhinitis is a common upper airway disease caused by hypersensitivity to various aeroalle... more Allergic rhinitis is a common upper airway disease caused by hypersensitivity to various aeroallergens. It causes increased inflammation throughout the body and may be complicated by other otolaryngological pathologies such as chronic hyperplastic eosinophilic sinusitis, nasal polyposis, and serous otitis media. Allergic rhinitis is an IgE-mediated disease and immunotherapy can be a possible approach for patients to limit the use of antihistamines and corticosteroids. There is evidence that allergen immunotherapy can prevent the development of new sensitizations and reduce the risk of later development of asthma in patients with allergic rhinitis. However, some patients do not benefit from this approach and the efficacy of immunotherapy in reducing the severity and relapse of symptoms is still a matter of debate. This review highlights new aspects of allergic rhinitis with a particular focus on the impact of sexual dimorphism on the disease manifestation and efficacy to the allergen...
Supplementary Figure 1. Representative plots illustrating analysis of tumor-specific CD8+ T cell ... more Supplementary Figure 1. Representative plots illustrating analysis of tumor-specific CD8+ T cell response in TRAMP and KitWsh-TRAMP mice. Supplementary Figure 2. CD8+T cells from PDLN and prostates of KitWsh-TRAMP mice are responsive. Supplementary Figure 3. Quantification of MCs or T cells after reconstitution of depletion, respectively. Supplementary Figure 4. Flow cytometry identification of T cells in spleen and prostate of TRAMP and KitWsh-TRAMP mice. Supplementary Figure 5. Flow cytometry identification of myeloid cells in spleen and prostate of TRAMP and KitWsh-TRAMP mice. Supplementary Figure 6. MCs and PMN-MDSC can interact via CD40L-CD40 in TRAMP mice. Supplementary Figure 7. Wild type and CD40L-/- BMMC are equally functional, but CD8+T cells from PDLN and prostates of KitWsh-TRAMP mice reconstituted with BMMC CD40L-/- are still responsive. Supplementary Figure 8. MCs, CD40L and CD33 co-localize in human tumor prostate cancer samples. Supplementary Figure 9. Correlation be...
MDSC accumulation in CT-26 tumor bearing mice and migration in response to mast cells and to cond... more MDSC accumulation in CT-26 tumor bearing mice and migration in response to mast cells and to conditioned media from colon cancer cell line.
Inflammation plays crucial roles at different stages of tumor development and may lead to the fai... more Inflammation plays crucial roles at different stages of tumor development and may lead to the failure of immune surveillance and immunotherapy. Myeloid-derived suppressor cells (MDSC) are one of the major components of the immune-suppressive network that favors tumor growth, and their interaction with mast cells is emerging as critical for the outcome of the tumor-associated immune response. Herein, we showed the occurrence of cell-to-cell interactions between MDSCs and mast cells in the mucosa of patients with colon carcinoma and in the colon and spleen of tumor-bearing mice. Furthermore, we demonstrated that the CT-26 colon cancer cells induced the accumulation of CD11b+Gr1+ immature MDSCs and the recruitment of protumoral mast cells at the tumor site. Using ex vivo analyses, we showed that mast cells have the ability to increase the suppressive properties of spleen-derived monocytic MDSCs, through a mechanism involving IFNγ and nitric oxide production. In addition, we demonstrate...
Common variable immunodeficiency (CVID) is a predominantly antibody deficiency and is one of the ... more Common variable immunodeficiency (CVID) is a predominantly antibody deficiency and is one of the most common primary immunodeficiencies in adulthood. Replacement therapy with Ig has significantly reduced infectious complications; however, malignant, autoimmune, and inflammatory diseases are still current major causes of morbidity and mortality. In recent years, interest has increased regarding allergic manifestations that may be associated with primary immunodeficiencies; however, no data are currently available on chronic spontaneous urticaria (CSU). In this report, the authors describe CSU in patients with CVID attending their centre. Three CVID patients were affected by CSU and were unresponsive to antihistamines. Patients were screened for the presence of serum autoreactivity by an autologous serum skin test; only one patient was positive for serum autoreactivity. The serum of this patient was found to induce CD63 upregulation on basophils and degranulation of LAD2 mast cells. A...
Fatal neuroendocrine prostate cancer (NEPC) often emerges in patients relapsing after hormone the... more Fatal neuroendocrine prostate cancer (NEPC) often emerges in patients relapsing after hormone therapies. Besides, de novo NEPC can rarely occur in treatment-naïve patients. Treatment-related and de-novo NEPC have different genomic alterations but share a common transcriptional profile. Investigating the tumor microenvironment, we recently found that mast cells (MCs) accumulate within hormone-sensitive prostate cancer favoring its growth, whereas are excluded by de-novo NEPC both in patients and in the transgenic TRAMP spontaneous mouse model. TRAMP mice backcrossed with MCs-deficient KitWsh mice showed increased frequency of de-novo NEPC. The frequency of de-novo NEPC similarly raised also in TRAMP mice deficient for the matricellular protein osteopontin (OPN). Reconstituting KitWsh-TRAMP mice with wild type, but not with OPN-deficient, MCs lowered the frequency of NEPC to that of untreated TRAMP mice. We found that MCs stain positive for OPN in tumor sections and in vitro cultures, but release a tiny amount of OPN in supernatants if compared to NEPC cells. Notably, OPN has both secreted (sOPN) and intracellular (iOPN) forms; the latter can bind to MyD88 and regulate the signaling downstream toll-like receptors (TLRs). In vitro, wild type, but not OPN-/- or MyD88-/-, MCs inhibited the proliferation of NEPC cells. Also, in silico analyses showed that genes related to inflammatory response and TLRs signaling are down regulated in human and murine NEPC.Our data suggest that TLRs/MyD88/iOPN-mediated pathways induce MCs to release factor(s) able to restrain NEPC. Further studies are required to molecularly dissect this novel function of MCs, to identify actionable targets against NEPC. Citation Format: Roberta Sulsenti, Barbara Frossi, Valeria Cancila, Claudia Enriquez, Renata Ferri, Sabina Sangaletti, Claudio Tripodo, Carlo Emilio Pucillo, Mario Paolo Colombo, Elena Jachetti. The protective role of mast cells against neuroendocrine prostate cancer depends on the release of cytokines mediated by intracellular osteopontin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2556.
Supplementary Figure 1. Representative plots illustrating analysis of tumor-specific CD8+ T cell ... more Supplementary Figure 1. Representative plots illustrating analysis of tumor-specific CD8+ T cell response in TRAMP and KitWsh-TRAMP mice. Supplementary Figure 2. CD8+T cells from PDLN and prostates of KitWsh-TRAMP mice are responsive. Supplementary Figure 3. Quantification of MCs or T cells after reconstitution of depletion, respectively. Supplementary Figure 4. Flow cytometry identification of T cells in spleen and prostate of TRAMP and KitWsh-TRAMP mice. Supplementary Figure 5. Flow cytometry identification of myeloid cells in spleen and prostate of TRAMP and KitWsh-TRAMP mice. Supplementary Figure 6. MCs and PMN-MDSC can interact via CD40L-CD40 in TRAMP mice. Supplementary Figure 7. Wild type and CD40L-/- BMMC are equally functional, but CD8+T cells from PDLN and prostates of KitWsh-TRAMP mice reconstituted with BMMC CD40L-/- are still responsive. Supplementary Figure 8. MCs, CD40L and CD33 co-localize in human tumor prostate cancer samples. Supplementary Figure 9. Correlation between MC-genes and MDSC-activity genes in human prostate cancer data sets. Supplementary Figure 10. MC/PMN-MDSC signatures outperform random signatures of the same length.
OX40L is expressed by many cell types, including antigen presenting cells (APCs), T cells, vascul... more OX40L is expressed by many cell types, including antigen presenting cells (APCs), T cells, vascular endothelial cells, mast cells (MCs), and natural killer cells. The importance of OX40L:OX40 interactions and the OX40L signaling is crucial for the homeostasis and for the modulation of the effector functions of the immune system. However, the lack of non-murine/non-IgG commercially available OX40L-triggering antibodies and the potential signal cross-contamination caused by the binding to the FcγRs co-expressed by several immune cells have limited the study of the OX40L-signaling cascade. We recently characterized the functions and described the molecular events, which follow the engagement of OX40L in MCs, by the use of the soluble OX40 molecule, able to mimic the regulatory T cell-driven engagement of MC-OX40L. This molecule enables signaling studies in MCs with any requirement for OX40-expressing cells. Using this unique reagent, we determined the modality and the extent by which the engagement of OX40L in MCs influences the IgE-dependent MC degranulation. This tool may find a potential application for signaling studies of other OX40L-expressing populations other than MCs, mainly APCs, with similar approaches we reported for the study of OX40L cascade.
Allergic rhinitis is a common upper airway disease caused by hypersensitivity to various aeroalle... more Allergic rhinitis is a common upper airway disease caused by hypersensitivity to various aeroallergens. It causes increased inflammation throughout the body and may be complicated by other otolaryngological pathologies such as chronic hyperplastic eosinophilic sinusitis, nasal polyposis, and serous otitis media. Allergic rhinitis is an IgE-mediated disease and immunotherapy can be a possible approach for patients to limit the use of antihistamines and corticosteroids. There is evidence that allergen immunotherapy can prevent the development of new sensitizations and reduce the risk of later development of asthma in patients with allergic rhinitis. However, some patients do not benefit from this approach and the efficacy of immunotherapy in reducing the severity and relapse of symptoms is still a matter of debate. This review highlights new aspects of allergic rhinitis with a particular focus on the impact of sexual dimorphism on the disease manifestation and efficacy to the allergen...
Supplementary Figure 1. Representative plots illustrating analysis of tumor-specific CD8+ T cell ... more Supplementary Figure 1. Representative plots illustrating analysis of tumor-specific CD8+ T cell response in TRAMP and KitWsh-TRAMP mice. Supplementary Figure 2. CD8+T cells from PDLN and prostates of KitWsh-TRAMP mice are responsive. Supplementary Figure 3. Quantification of MCs or T cells after reconstitution of depletion, respectively. Supplementary Figure 4. Flow cytometry identification of T cells in spleen and prostate of TRAMP and KitWsh-TRAMP mice. Supplementary Figure 5. Flow cytometry identification of myeloid cells in spleen and prostate of TRAMP and KitWsh-TRAMP mice. Supplementary Figure 6. MCs and PMN-MDSC can interact via CD40L-CD40 in TRAMP mice. Supplementary Figure 7. Wild type and CD40L-/- BMMC are equally functional, but CD8+T cells from PDLN and prostates of KitWsh-TRAMP mice reconstituted with BMMC CD40L-/- are still responsive. Supplementary Figure 8. MCs, CD40L and CD33 co-localize in human tumor prostate cancer samples. Supplementary Figure 9. Correlation be...
MDSC accumulation in CT-26 tumor bearing mice and migration in response to mast cells and to cond... more MDSC accumulation in CT-26 tumor bearing mice and migration in response to mast cells and to conditioned media from colon cancer cell line.
Inflammation plays crucial roles at different stages of tumor development and may lead to the fai... more Inflammation plays crucial roles at different stages of tumor development and may lead to the failure of immune surveillance and immunotherapy. Myeloid-derived suppressor cells (MDSC) are one of the major components of the immune-suppressive network that favors tumor growth, and their interaction with mast cells is emerging as critical for the outcome of the tumor-associated immune response. Herein, we showed the occurrence of cell-to-cell interactions between MDSCs and mast cells in the mucosa of patients with colon carcinoma and in the colon and spleen of tumor-bearing mice. Furthermore, we demonstrated that the CT-26 colon cancer cells induced the accumulation of CD11b+Gr1+ immature MDSCs and the recruitment of protumoral mast cells at the tumor site. Using ex vivo analyses, we showed that mast cells have the ability to increase the suppressive properties of spleen-derived monocytic MDSCs, through a mechanism involving IFNγ and nitric oxide production. In addition, we demonstrate...
Common variable immunodeficiency (CVID) is a predominantly antibody deficiency and is one of the ... more Common variable immunodeficiency (CVID) is a predominantly antibody deficiency and is one of the most common primary immunodeficiencies in adulthood. Replacement therapy with Ig has significantly reduced infectious complications; however, malignant, autoimmune, and inflammatory diseases are still current major causes of morbidity and mortality. In recent years, interest has increased regarding allergic manifestations that may be associated with primary immunodeficiencies; however, no data are currently available on chronic spontaneous urticaria (CSU). In this report, the authors describe CSU in patients with CVID attending their centre. Three CVID patients were affected by CSU and were unresponsive to antihistamines. Patients were screened for the presence of serum autoreactivity by an autologous serum skin test; only one patient was positive for serum autoreactivity. The serum of this patient was found to induce CD63 upregulation on basophils and degranulation of LAD2 mast cells. A...
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Papers by Barbara Frossi