High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot
Background Prostate cancer (PCa) has a profoundly immunosuppressive microenvironment and is commonly immune excluded with few infiltrative lymphocytes and low levels of immune activation. High-dose radiation has been demonstrated to stimulate the immune system in various human solid tumors. We hypot...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2020-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/1/e000792.full |
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| author | Shahneen Sandhu Paul J Neeson Simon P Keam Heloise Halse Thu Nguyen Minyu Wang Nicolas Van Kooten Losio Catherine Mitchell Franco Caramia David J Byrne Sue Haupt Georgina Ryland Phillip K Darcy Piers Blombery Ygal Haupt Scott G Williams |
| author_facet | Shahneen Sandhu Paul J Neeson Simon P Keam Heloise Halse Thu Nguyen Minyu Wang Nicolas Van Kooten Losio Catherine Mitchell Franco Caramia David J Byrne Sue Haupt Georgina Ryland Phillip K Darcy Piers Blombery Ygal Haupt Scott G Williams |
| author_sort | Shahneen Sandhu |
| collection | DOAJ |
| description | Background Prostate cancer (PCa) has a profoundly immunosuppressive microenvironment and is commonly immune excluded with few infiltrative lymphocytes and low levels of immune activation. High-dose radiation has been demonstrated to stimulate the immune system in various human solid tumors. We hypothesized that localized radiation therapy, in the form of high dose-rate brachytherapy (HDRBT), would overcome immune suppression in PCa.Methods To investigate whether HDRBT altered prostate immune context, we analyzed preradiation versus postradiation human tissue from a cohort of 24 patients with localized PCa that received HDRBT as primary treatment (RadBank cohort). We performed Nanostring immune gene expression profiling, digital spatial profiling, and high-throughput immune cell multiplex immunohistochemistry analysis. We also resolved tumor and nontumor zones in spatial and bioinformatic analyses to explore the immunological response.Results Nanostring immune profiling revealed numerous immune checkpoint molecules (eg, B7-H3, CTLA4, PDL1, and PDL2) and TGFβ levels were increased in response to HDRBT. We used a published 16-gene tumor inflammation signature (TIS) to divide tumors into distinct immune activation states (high:hot, intermediate and low:cold) and showed that most localized PCa are cold tumors pre-HDRBT. Crucially, HDRBT converted 80% of these ‘cold’-phenotype tumors into an ‘intermediate’ or ‘hot’ class. We used digital spatial profiling to show these HDRBT-induced changes in prostate TIS scores were derived from the nontumor regions. Furthermore, these changes in TIS were also associated with pervasive changes in immune cell density and spatial relationships—in particular, between T cell subsets and antigen presenting cells. We identified an increased density of CD4+ FOXP3+ T cells, CD68+ macrophages and CD68+ CD11c+ dendritic cells in response to HDRBT. The only subset change specific to tumor zones was PDL1- macrophages. While these immune responses were heterogeneous, HDRBT induced significant changes in immune cell associations, including a gained T cell and HMWCK+ PDL1+ interaction in tumor zones.Conclusion In conclusion, we showed HDRBT converted “cold” prostate tumors into more immunologically activated “hot” tissues, with accompanying spatially organized immune infiltrates and signaling changes. Understanding and potentially harnessing these changes will have widespread implications for the future treatment of localized PCa, including rational use of combination radio-immunotherapy. |
| format | Article |
| id | doaj-art-80d24ee76e7f4079aca96e405ba2bd33 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-05-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-80d24ee76e7f4079aca96e405ba2bd332025-08-20T02:13:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-05-018110.1136/jitc-2020-000792High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hotShahneen Sandhu0Paul J Neeson1Simon P Keam2Heloise Halse3Thu Nguyen4Minyu Wang5Nicolas Van Kooten Losio6Catherine Mitchell7Franco Caramia8David J Byrne9Sue Haupt10Georgina Ryland11Phillip K Darcy12Piers Blombery13Ygal Haupt14Scott G Williams15Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, AustraliaAff2 grid.1055.10000000403978434Cancer ImmunologyPeter MacCallum Cancer Centre Melbourne VIC Australia1 Cancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaCancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaCancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaCancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia1 Cancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaDepartment of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaTumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia4 Pathology Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaSir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, AustraliaPathology Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia1 Cancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaDepartment of Clinical Haematology, Peter MacCallum Cancer Centre & The Royal Melbourne Hospital, Parkville, Victoria, AustraliaSir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia6 Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, AustraliaBackground Prostate cancer (PCa) has a profoundly immunosuppressive microenvironment and is commonly immune excluded with few infiltrative lymphocytes and low levels of immune activation. High-dose radiation has been demonstrated to stimulate the immune system in various human solid tumors. We hypothesized that localized radiation therapy, in the form of high dose-rate brachytherapy (HDRBT), would overcome immune suppression in PCa.Methods To investigate whether HDRBT altered prostate immune context, we analyzed preradiation versus postradiation human tissue from a cohort of 24 patients with localized PCa that received HDRBT as primary treatment (RadBank cohort). We performed Nanostring immune gene expression profiling, digital spatial profiling, and high-throughput immune cell multiplex immunohistochemistry analysis. We also resolved tumor and nontumor zones in spatial and bioinformatic analyses to explore the immunological response.Results Nanostring immune profiling revealed numerous immune checkpoint molecules (eg, B7-H3, CTLA4, PDL1, and PDL2) and TGFβ levels were increased in response to HDRBT. We used a published 16-gene tumor inflammation signature (TIS) to divide tumors into distinct immune activation states (high:hot, intermediate and low:cold) and showed that most localized PCa are cold tumors pre-HDRBT. Crucially, HDRBT converted 80% of these ‘cold’-phenotype tumors into an ‘intermediate’ or ‘hot’ class. We used digital spatial profiling to show these HDRBT-induced changes in prostate TIS scores were derived from the nontumor regions. Furthermore, these changes in TIS were also associated with pervasive changes in immune cell density and spatial relationships—in particular, between T cell subsets and antigen presenting cells. We identified an increased density of CD4+ FOXP3+ T cells, CD68+ macrophages and CD68+ CD11c+ dendritic cells in response to HDRBT. The only subset change specific to tumor zones was PDL1- macrophages. While these immune responses were heterogeneous, HDRBT induced significant changes in immune cell associations, including a gained T cell and HMWCK+ PDL1+ interaction in tumor zones.Conclusion In conclusion, we showed HDRBT converted “cold” prostate tumors into more immunologically activated “hot” tissues, with accompanying spatially organized immune infiltrates and signaling changes. Understanding and potentially harnessing these changes will have widespread implications for the future treatment of localized PCa, including rational use of combination radio-immunotherapy.https://jitc.bmj.com/content/8/1/e000792.full |
| spellingShingle | Shahneen Sandhu Paul J Neeson Simon P Keam Heloise Halse Thu Nguyen Minyu Wang Nicolas Van Kooten Losio Catherine Mitchell Franco Caramia David J Byrne Sue Haupt Georgina Ryland Phillip K Darcy Piers Blombery Ygal Haupt Scott G Williams High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot Journal for ImmunoTherapy of Cancer |
| title | High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot |
| title_full | High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot |
| title_fullStr | High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot |
| title_full_unstemmed | High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot |
| title_short | High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot |
| title_sort | high dose rate brachytherapy of localized prostate cancer converts tumors from cold to hot |
| url | https://jitc.bmj.com/content/8/1/e000792.full |
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