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News Article | May 15, 2017
Site: www.eurekalert.org

'Tumour-trained' immune cells - which have the potential to kill cancer cells - have been seen moving from one tumour to another for the first time. The new findings, which were uncovered by scientists at Australia's Garvan Institute of Medical Research, shed light on how immune therapies for cancer might work, and suggest new approaches to developing anti-cancer immune therapies. The study, which was carried out in mice, is published today in the Proceedings of the National Academy of Sciences USA (PNAS). Metastatic cancer, in which cancer has spread to other sites beyond the primary tumour, is responsible for almost all cancer deaths, and treatment options remain very limited. New immune therapies that help the body's own immune T cells to attack cancer cells within tumours are showing promise in metastatic cancer -- yet little is understood about how these therapies function. "We know that T cells and other immune cells accumulate inside tumours -- but until now we've known very little about what happens next. How does the environment within the tumour change the cells? Do they leave the tumour? Which types of immune cells leave? Where do they go, and why?" says Dr Tatyana Chtanova, head of the Innate and Tumour Immunology lab in Garvan's Immunology Division, who led the research. To watch 'tumour-trained' immune cells travelling through the body, Dr Chtanova and her team used an innovative 'photoconversion' strategy -- in which all the cells in a mouse are labelled with a green fluorescent compound, and only those within a tumour (including immune cells) are turned to red by shining a bright light on the tumour. "Before, we could only guess at which immune cells were leaving tumours," says Dr Chtanova, "so to see these red cells moving in a sea of green, as they exited a tumour and travelled through the body, was remarkable. "We saw immune cells leaving the tumour and moving into lymph nodes - and, importantly, we could see immune cells moving out of one tumour and into another, distant tumour." The researchers were surprised to see that the mix of immune cells leaving tumours was sharply different to the mix of immune cells going in. "We found, unexpectedly, that T cells were the main immune cells to exit tumours and move to lymph nodes and other tumours - even though they represent only a fraction of the immune cells that enter tumours," Dr Chtanova notes, "and some classes of T cell, such as CD8+ effector T cells which promote tumour destruction, were more likely to exit the tumour. "This tells us that there's strong control over the tumour-exiting process." Importantly, the T cells that had been exposed to the tumour's 'microenvironment' and then exited the tumour were more activated, and had a stronger cytotoxic (cell-killing) activity, than those that did not enter the tumour. "What we suspect is happening is that, within the tumour, these T cells are acquiring knowledge about the cancer that helps them to seek and destroy tumour cells. "It's possible that these T cells 'on patrol' -- which leave one tumour and move to another -- are using their new-found knowledge to attack cancerous cells in the second tumour." The research team are now working on ways to prompt activated T cells to exit tumours in greater numbers. "Ultimately, we're working to understand more deeply the relationships between immune and cancer cells, so that we can design approaches to empower the immune system to destroy cancer," Dr Chtanova adds.


News Article | May 16, 2017
Site: www.sciencedaily.com

'Tumour-trained' immune cells -- which have the potential to kill cancer cells -- have been seen moving from one tumour to another for the first time. The new findings, which were uncovered by scientists at Australia's Garvan Institute of Medical Research, shed light on how immune therapies for cancer might work, and suggest new approaches to developing anti-cancer immune therapies. The study, which was carried out in mice, is published today in the Proceedings of the National Academy of Sciences. Metastatic cancer, in which cancer has spread to other sites beyond the primary tumour, is responsible for almost all cancer deaths, and treatment options remain very limited. New immune therapies that help the body's own immune T cells to attack cancer cells within tumours are showing promise in metastatic cancer -- yet little is understood about how these therapies function. "We know that T cells and other immune cells accumulate inside tumours -- but until now we've known very little about what happens next. How does the environment within the tumour change the cells? Do they leave the tumour? Which types of immune cells leave? Where do they go, and why?" says Dr Tatyana Chtanova, head of the Innate and Tumour Immunology lab in Garvan's Immunology Division, who led the research. To watch 'tumour-trained' immune cells travelling through the body, Dr Chtanova and her team used an innovative 'photoconversion' strategy -- in which all the cells in a mouse are labelled with a green fluorescent compound, and only those within a tumour (including immune cells) are turned to red by shining a bright light on the tumour. "Before, we could only guess at which immune cells were leaving tumours," says Dr Chtanova, "so to see these red cells moving in a sea of green, as they exited a tumour and travelled through the body, was remarkable. "We saw immune cells leaving the tumour and moving into lymph nodes -- and, importantly, we could see immune cells moving out of one tumour and into another, distant tumour." The researchers were surprised to see that the mix of immune cells leaving tumours was sharply different to the mix of immune cells going in. "We found, unexpectedly, that T cells were the main immune cells to exit tumours and move to lymph nodes and other tumours -- even though they represent only a fraction of the immune cells that enter tumours," Dr Chtanova notes, "and some classes of T cell, such as CD8+ effector T cells which promote tumour destruction, were more likely to exit the tumour. "This tells us that there's strong control over the tumour-exiting process." Importantly, the T cells that had been exposed to the tumour's 'microenvironment' and then exited the tumour were more activated, and had a stronger cytotoxic (cell-killing) activity, than those that did not enter the tumour. "What we suspect is happening is that, within the tumour, these T cells are acquiring knowledge about the cancer that helps them to seek and destroy tumour cells. "It's possible that these T cells 'on patrol' -- which leave one tumour and move to another -- are using their new-found knowledge to attack cancerous cells in the second tumour." The research team are now working on ways to prompt activated T cells to exit tumours in greater numbers. "Ultimately, we're working to understand more deeply the relationships between immune and cancer cells, so that we can design approaches to empower the immune system to destroy cancer," Dr Chtanova adds.


News Article | May 16, 2017
Site: www.biosciencetechnology.com

'Tumor-trained' immune cells - which have the potential to kill cancer cells - have been seen moving from one tumor to another for the first time. The new findings, which were uncovered by scientists at Australia's Garvan Institute of Medical Research, shed light on how immune therapies for cancer might work, and suggest new approaches to developing anti-cancer immune therapies. The study, which was carried out in mice, is published in the Proceedings of the National Academy of Sciences USA (PNAS). Metastatic cancer, in which cancer has spread to other sites beyond the primary tumor, is responsible for almost all cancer deaths, and treatment options remain very limited. New immune therapies that help the body's own immune T cells to attack cancer cells within tumors are showing promise in metastatic cancer -- yet little is understood about how these therapies function. "We know that T cells and other immune cells accumulate inside tumors -- but until now we've known very little about what happens next. How does the environment within the tumor change the cells? Do they leave the tumor? Which types of immune cells leave? Where do they go, and why?" said Dr. Tatyana Chtanova, head of the Innate and Tumor Immunology lab in Garvan's Immunology Division, who led the research. To watch 'tumor-trained' immune cells travelling through the body, Chtanova and her team used an innovative 'photoconversion' strategy -- in which all the cells in a mouse are labelled with a green fluorescent compound, and only those within a tumor (including immune cells) are turned to red by shining a bright light on the tumor. "Before, we could only guess at which immune cells were leaving tumors," said Chtanova, "so to see these red cells moving in a sea of green, as they exited a tumor and travelled through the body, was remarkable. "We saw immune cells leaving the tumor and moving into lymph nodes - and, importantly, we could see immune cells moving out of one tumor and into another, distant tumor." The researchers were surprised to see that the mix of immune cells leaving tumors was sharply different to the mix of immune cells going in. "We found, unexpectedly, that T cells were the main immune cells to exit tumors and move to lymph nodes and other tumors - even though they represent only a fraction of the immune cells that enter tumors," Chtanova noted, "and some classes of T cell, such as CD8+ effector T cells which promote tumor destruction, were more likely to exit the tumor. "This tells us that there's strong control over the tumor-exiting process." Importantly, the T cells that had been exposed to the tumor's 'microenvironment' and then exited the tumor were more activated, and had a stronger cytotoxic (cell-killing) activity, than those that did not enter the tumor. "What we suspect is happening is that, within the tumor, these T cells are acquiring knowledge about the cancer that helps them to seek and destroy tumor cells. "It's possible that these T cells 'on patrol' -- which leave one tumor and move to another -- are using their new-found knowledge to attack cancerous cells in the second tumor." The research team are now working on ways to prompt activated T cells to exit tumors in greater numbers. "Ultimately, we're working to understand more deeply the relationships between immune and cancer cells, so that we can design approaches to empower the immune system to destroy cancer," Chtanova added.


Salvador F.,Autonomous University of Barcelona | Sanchez-Montalva A.,Autonomous University of Barcelona | Martinez-Gallo M.,Immunology Division | Sala-Cunill A.,Allergy Section | And 6 more authors.
Clinical Infectious Diseases | Year: 2015

Background. Benznidazole is the drug of choice for Chagas disease. The major drawback of this drug is the high adverse events rate, being cutaneous reactions the most frequent one, leading to definitive withdrawal of treatment in 15%-30% of patients. Methods. Prospective observational study where adult Chagas disease patients accepting to receive benznidazole (100 mg/8 hours for 60 days) were included. The objective was to characterize the skin toxicity of benznidazole in patients with Chagas disease, determine the serum cytokine profile, and evaluate the potential association with specific HLA alleles and benznidazole concentration. Serum cytokine levels were measured at day 0, 15, and 60 of treatment. Class I and II HLA alleles were determined. When cutaneous reaction was detected, a skin biopsy was performed. Serum benznidazole concentration was determined at the time of cutaneous reaction, or at day 15 of treatment. Results. Fifty-two patients were included, 20(38.5%) had cutaneous reaction, and median time of appearance was 9 days. Skin biopsies showed histopathological findings consistent with drug eruption. Patients with cutaneous drug-reaction had higher proportion of eosinophilia during treatment, and higher interleukin (IL)-5 and IL-10 serum concentrations at day 15 of treatment than those without cutaneous reaction. Treatment interruption (that included moderate-severe cutaneous reactions) was more frequent in patients carrying HLA-B∗3505 allele (45.5% vs 15.4%, P =. 033). No differences in benznidazole serum concentration were found. Conclusions. Benznidazole related cutaneous reaction rate is high, and it was produced by a delayed hypersensitivity reaction with a Th2 response. Carrying HLA-B∗3505 allele could be associated with moderate-severe cutaneous reaction. © 2015 The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.


PubMed | HIGH-TECH, Immunology Division., Allergy Section, Autonomous University of Barcelona and University of Barcelona
Type: Journal Article | Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2015

Benznidazole is the drug of choice for Chagas disease. The major drawback of this drug is the high adverse events rate, being cutaneous reactions the most frequent one, leading to definitive withdrawal of treatment in 15%-30% of patients.Prospective observational study where adult Chagas disease patients accepting to receive benznidazole (100 mg/8 hours for 60 days) were included. The objective was to characterize the skin toxicity of benznidazole in patients with Chagas disease, determine the serum cytokine profile, and evaluate the potential association with specific HLA alleles and benznidazole concentration. Serum cytokine levels were measured at day 0, 15, and 60 of treatment. Class I and II HLA alleles were determined. When cutaneous reaction was detected, a skin biopsy was performed. Serum benznidazole concentration was determined at the time of cutaneous reaction, or at day 15 of treatment.Fifty-two patients were included, 20(38.5%) had cutaneous reaction, and median time of appearance was 9 days. Skin biopsies showed histopathological findings consistent with drug eruption. Patients with cutaneous drug-reaction had higher proportion of eosinophilia during treatment, and higher interleukin (IL)-5 and IL-10 serum concentrations at day 15 of treatment than those without cutaneous reaction. Treatment interruption (that included moderate-severe cutaneous reactions) was more frequent in patients carrying HLA-B*3505 allele (45.5% vs 15.4%, P = .033). No differences in benznidazole serum concentration were found.Benznidazole related cutaneous reaction rate is high, and it was produced by a delayed hypersensitivity reaction with a Th2 response. Carrying HLA-B*3505 allele could be associated with moderate-severe cutaneous reaction.


Rodriguez G.M.,Immunology division | Bobbala D.,Immunology division | Serrano D.,Immunology division | Mayhue M.,Immunology division | And 8 more authors.
OncoImmunology | Year: 2016

Cancers can escape immunesurveillance by diminishing the expression of MHC class-I molecules (MHC-I) and components of the antigen-processing machinery (APM). Developing new approaches to reverse these defects could boost the efforts to restore antitumor immunity. Recent studies have shown that the expression of MHC-I and antigen-processing molecules is transcriptionally regulated by NOD-like receptor CARD domain containing 5 (NLRC5). To investigate whether NLRC5 could be used to improve tumor immunogenicity, we established stable lines of B16-F10 melanoma cells expressing NLRC5 (B16-5), the T cell co-stimulatory molecule CD80 (B16-CD80) or both (B16-5/80). Cells harboring NLRC5 constitutively expressed MHC-I and LMP2, LMP7 and TAP1 genes of the APM. The B16-5 cells efficiently presented the melanoma antigenic peptide gp10025–33 to Pmel-1 TCR transgenic CD8+ T cells and induced their proliferation. In the presence of CD80, B16-5 cells stimulated Pmel-1 cells even without the addition of gp100 peptide, indicating that NLRC5 facilitated the processing and presentation of endogenous tumor antigen. Upon subcutaneous implantation, B16-5 cells showed markedly reduced tumor growth in C57BL/6 hosts but not in immunodeficient hosts, indicating that the NLRC5-expressing tumor cells elicited antitumor immunity. Following intravenous injection, B16-5 and B16-5/80 cells formed fewer lung tumor foci compared to control cells. In mice depleted of CD8+ T cells, B16-5 cells formed large subcutaneous and lung tumors. Finally, immunization with irradiated B16-5 cells conferred protection against challenge by parental B16 cells. Collectively, our findings indicate that NLRC5 could be exploited to restore tumor immunogenicity and to stimulate protective antitumor immunity. © 2016 The Author(s). Published with license by Taylor & Francis Group, LLC


Kandhi R.,Immunology Division | Bobbala D.,Immunology Division | Yeganeh M.,Immunology Division | Mayhue M.,Immunology Division | And 2 more authors.
Cytokine | Year: 2015

Suppressor of cytokine signaling 1 (SOCS1) is an indispensable regulator of IFNγ signaling and has been implicated in the regulation of liver fibrosis. However, it is not known whether SOCS1 mediates its anti-fibrotic functions in the liver directly, or via modulating IFNγ, which has been implicated in attenuating hepatic fibrosis. Additionally, it is possible that SOCS1 controls liver fibrosis by regulating hepatic stellate cells (HSC), a key player in fibrogenic response. While the activation pathways of HSCs have been well characterized, the regulatory mechanisms are not yet clear. The goals of this study were to dissociate IFNγ-dependent and SOCS1-mediated regulation of hepatic fibrogenic response, and to elucidate the regulatory functions of SOCS1 in HSC activation. Liver fibrosis was induced in Socs1-/-Ifng-/- mice with dimethylnitrosamine or carbon tetrachloride. Ifng-/- and C57BL/6 mice served as controls. Following fibrogenic treatments, Socs1-/-Ifng-/- mice showed elevated serum ALT levels and increased liver fibrosis compared to Ifng-/- mice. The latter group showed higher ALT levels and fibrosis than C57BL/6 controls. The livers of SOCS1-deficient mice showed bridging fibrosis, which was associated with increased accumulation of myofibroblasts and abundant collagen deposition. SOCS1-deficient livers showed increased expression of genes coding for smooth muscle actin, collagen, and enzymes involved in remodeling the extracellular matrix, namely matrix metalloproteinases and tissue inhibitor of metalloproteinases. Primary HSCs from SOCS1-deficient mice showed increased proliferation in response to growth factors such as HGF, EGF and PDGF, and the fibrotic livers of SOCS1-deficient mice showed increased expression of the Pdgfb gene. Taken together, these data indicate that SOCS1 controls liver fibrosis independently of IFNγ and that part of this regulation may occur via regulating HSC proliferation and limiting growth factor availability. © 2015.

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