Mcdonnell a M Currie a J Brown M Kania K Wylie B Cleaver a Lake R and Robinson B W S Tumor Cells Rather Than Dendritic Cells Deliver Antigen to the Lymph Node For Cross Presentation Oncoimmunology 1 Pp 840 846, Sep 1, 2012
It is widely accepted that generation of tumor specific CD8+ T-cell responses occur via cross-pri... more It is widely accepted that generation of tumor specific CD8+ T-cell responses occur via cross-priming; however the source of tumor antigen for this event is unknown. We examined the source and form of tumor antigen required for cross-presentation in the local lymph node (LN) using a syngeneic mouse tumor model expressing a marker antigen. We found that cross-presentation of this model tumor antigen in the LN is dependent on continuous traffic of antigen from the tumor site, but without any detectable migration of tumor resident dendritic cells (DCs). Instead, small numbers of tumor cells metastasize to local LNs where they are exposed to a localized CTL attack, resulting in delivery of tumor antigen into the cross-presentation pathway.
The question of which dendritic cells (DCs) cross-present peripheral tumor antigens remains unans... more The question of which dendritic cells (DCs) cross-present peripheral tumor antigens remains unanswered. We assessed the ability of multiple skin-derived and lymphoid resident DCs to perform this function in a novel orthotopic murine melanoma model where tumor establishment and expansion is within the skin. Two migratory populations defined as CD103(-)XCR1(+) and CD103(+)XCR1(+) efficiently cross-presented melanoma-derived antigen, with the CD103(-)XCR1(+) DCs surprisingly dominating this process. These results are critical for understanding how antitumor CD8(+) T cell immunity is coordinated to tumor antigens present within the skin.
The question of which dendritic cells (DCs) cross-present peripheral tumor antigens remains unans... more The question of which dendritic cells (DCs) cross-present peripheral tumor antigens remains unanswered. We assessed the ability of multiple skin-derived and lymphoid resident DCs to perform this function in a novel orthotopic murine melanoma model where tumor establishment and expansion is within the skin. Two migratory populations defined as CD103(-)XCR1(+) and CD103(+)XCR1(+) efficiently cross-presented melanoma-derived antigen, with the CD103(-)XCR1(+) DCs surprisingly dominating this process. These results are critical for understanding how antitumor CD8(+) T cell immunity is coordinated to tumor antigens present within the skin.
It is widely accepted that generation of tumor specific CD8+ T-cell responses occur via cross-pri... more It is widely accepted that generation of tumor specific CD8+ T-cell responses occur via cross-priming; however the source of tumor antigen for this event is unknown. We examined the source and form of tumor antigen required for cross-presentation in the local lymph node (LN) using a syngeneic mouse tumor model expressing a marker antigen. We found that cross-presentation of this model tumor antigen in the LN is dependent on continuous traffic of antigen from the tumor site, but without any detectable migration of tumor resident dendritic cells (DCs). Instead, small numbers of tumor cells metastasize to local LNs where they are exposed to a localized CTL attack, resulting in delivery of tumor antigen into the cross-presentation pathway.
Simian virus 40 (SV40) has been implicated in the development of several cancers including malign... more Simian virus 40 (SV40) has been implicated in the development of several cancers including malignant mesothelioma. A definitive role for the virus in human mesothelioma has not been unequivocally demonstrated but has been rigorously debated. The virus clearly has oncogenic potential: the TAg is one of the most potent transforming proteins known and acts synergistically with crocidolite asbestos to transform mesothelial cells. In this study, we show that SV40 oncogenes alone can cause malignant transformation and that asbestos-induced DNA damage and apoptosis occurs principally in cycling cells. After long-term exposure (up to 100 days) to both SV40 and asbestos, cells become resistant to stress-induced senescence. Significantly, these cells demonstrate resistance to chemotherapy-induced apoptosis. This finding has implications for the development of effective treatment options for patients with mesothelioma.
Tumor debulking surgery followed by adjuvant chemotherapy or radiotherapy is a standard treatment... more Tumor debulking surgery followed by adjuvant chemotherapy or radiotherapy is a standard treatment for many solid malignancies. Although this approach can be effective, it often has limited success against recurrent or metastatic cancers and new multimodality approaches are needed. Adjuvant immunotherapy is another potentially effective approach. We therefore tested the efficacy of the TLR7 agonist imiquimod (IMQ) combined with agonistic anti-CD40 in an incomplete debulking model of malignant mesothelioma. Established subcutaneous murine ABA-HA mesothelioma tumors in BALB/c mice were surgically debulked by 75% and treated with either: i) saline; ii) intratumoral IMQ; iii) systemic anti-CD40 antibody, or using a combination of IMQ and anti-CD40. Tumour growth and survival were monitored, and the role of anti-tumor CD4 and CD8 T cells in therapeutic responses was determined. The combination therapy of partial debulking surgery, IMQ and anti-CD40 significantly delayed tumor growth in a ...
Mcdonnell a M Currie a J Brown M Kania K Wylie B Cleaver a Lake R and Robinson B W S Tumor Cells Rather Than Dendritic Cells Deliver Antigen to the Lymph Node For Cross Presentation Oncoimmunology 1 Pp 840 846, Sep 1, 2012
It is widely accepted that generation of tumor specific CD8+ T-cell responses occur via cross-pri... more It is widely accepted that generation of tumor specific CD8+ T-cell responses occur via cross-priming; however the source of tumor antigen for this event is unknown. We examined the source and form of tumor antigen required for cross-presentation in the local lymph node (LN) using a syngeneic mouse tumor model expressing a marker antigen. We found that cross-presentation of this model tumor antigen in the LN is dependent on continuous traffic of antigen from the tumor site, but without any detectable migration of tumor resident dendritic cells (DCs). Instead, small numbers of tumor cells metastasize to local LNs where they are exposed to a localized CTL attack, resulting in delivery of tumor antigen into the cross-presentation pathway.
The question of which dendritic cells (DCs) cross-present peripheral tumor antigens remains unans... more The question of which dendritic cells (DCs) cross-present peripheral tumor antigens remains unanswered. We assessed the ability of multiple skin-derived and lymphoid resident DCs to perform this function in a novel orthotopic murine melanoma model where tumor establishment and expansion is within the skin. Two migratory populations defined as CD103(-)XCR1(+) and CD103(+)XCR1(+) efficiently cross-presented melanoma-derived antigen, with the CD103(-)XCR1(+) DCs surprisingly dominating this process. These results are critical for understanding how antitumor CD8(+) T cell immunity is coordinated to tumor antigens present within the skin.
The question of which dendritic cells (DCs) cross-present peripheral tumor antigens remains unans... more The question of which dendritic cells (DCs) cross-present peripheral tumor antigens remains unanswered. We assessed the ability of multiple skin-derived and lymphoid resident DCs to perform this function in a novel orthotopic murine melanoma model where tumor establishment and expansion is within the skin. Two migratory populations defined as CD103(-)XCR1(+) and CD103(+)XCR1(+) efficiently cross-presented melanoma-derived antigen, with the CD103(-)XCR1(+) DCs surprisingly dominating this process. These results are critical for understanding how antitumor CD8(+) T cell immunity is coordinated to tumor antigens present within the skin.
It is widely accepted that generation of tumor specific CD8+ T-cell responses occur via cross-pri... more It is widely accepted that generation of tumor specific CD8+ T-cell responses occur via cross-priming; however the source of tumor antigen for this event is unknown. We examined the source and form of tumor antigen required for cross-presentation in the local lymph node (LN) using a syngeneic mouse tumor model expressing a marker antigen. We found that cross-presentation of this model tumor antigen in the LN is dependent on continuous traffic of antigen from the tumor site, but without any detectable migration of tumor resident dendritic cells (DCs). Instead, small numbers of tumor cells metastasize to local LNs where they are exposed to a localized CTL attack, resulting in delivery of tumor antigen into the cross-presentation pathway.
Simian virus 40 (SV40) has been implicated in the development of several cancers including malign... more Simian virus 40 (SV40) has been implicated in the development of several cancers including malignant mesothelioma. A definitive role for the virus in human mesothelioma has not been unequivocally demonstrated but has been rigorously debated. The virus clearly has oncogenic potential: the TAg is one of the most potent transforming proteins known and acts synergistically with crocidolite asbestos to transform mesothelial cells. In this study, we show that SV40 oncogenes alone can cause malignant transformation and that asbestos-induced DNA damage and apoptosis occurs principally in cycling cells. After long-term exposure (up to 100 days) to both SV40 and asbestos, cells become resistant to stress-induced senescence. Significantly, these cells demonstrate resistance to chemotherapy-induced apoptosis. This finding has implications for the development of effective treatment options for patients with mesothelioma.
Tumor debulking surgery followed by adjuvant chemotherapy or radiotherapy is a standard treatment... more Tumor debulking surgery followed by adjuvant chemotherapy or radiotherapy is a standard treatment for many solid malignancies. Although this approach can be effective, it often has limited success against recurrent or metastatic cancers and new multimodality approaches are needed. Adjuvant immunotherapy is another potentially effective approach. We therefore tested the efficacy of the TLR7 agonist imiquimod (IMQ) combined with agonistic anti-CD40 in an incomplete debulking model of malignant mesothelioma. Established subcutaneous murine ABA-HA mesothelioma tumors in BALB/c mice were surgically debulked by 75% and treated with either: i) saline; ii) intratumoral IMQ; iii) systemic anti-CD40 antibody, or using a combination of IMQ and anti-CD40. Tumour growth and survival were monitored, and the role of anti-tumor CD4 and CD8 T cells in therapeutic responses was determined. The combination therapy of partial debulking surgery, IMQ and anti-CD40 significantly delayed tumor growth in a ...
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