Impact of pre‐therapy glioblastoma multiforme microenvironment on clinical response to autologous CMV‐specific T‐cell therapy
Abstract Objectives Clinical response to antibody‐based immunotherapies targeting checkpoint inhibitors is critically dependent on the tumor immune microenvironment (TIME). However, the precise impact of the TIME on adoptive cellular immunotherapy remains unexplored. Here we have conducted a long‐te...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2019-01-01
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| Series: | Clinical & Translational Immunology |
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| Online Access: | https://doi.org/10.1002/cti2.1088 |
| _version_ | 1828894236001435648 |
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| author | David G Walker Reshma Shakya Beth Morrison Michelle A Neller Katherine K Matthews John Nicholls Corey Smith Rajiv Khanna |
| author_facet | David G Walker Reshma Shakya Beth Morrison Michelle A Neller Katherine K Matthews John Nicholls Corey Smith Rajiv Khanna |
| author_sort | David G Walker |
| collection | DOAJ |
| description | Abstract Objectives Clinical response to antibody‐based immunotherapies targeting checkpoint inhibitors is critically dependent on the tumor immune microenvironment (TIME). However, the precise impact of the TIME on adoptive cellular immunotherapy remains unexplored. Here we have conducted a long‐term follow‐up analysis of patients with recurrent glioblastoma multiforme (GBM) who were treated with autologous CMV‐specific T‐cell therapy to delineate the potential impact of the TIME on their clinical response. Methods Multiplexed immunohistochemical analysis of CD3, PD‐L1 and Sox‐2 in GBM tissue biopsies obtained before autologous T‐cell therapy was carried out and correlated with long‐term survival of GBM patients adoptively treated with T‐cell therapy. Results Tumor microenvironment analyses revealed that the pre‐treatment cellular composition of the tumor tissue may influence the subsequent response to adoptive T‐cell therapy. GBM patients who showed prolonged overall survival following T‐cell therapy had a significantly lower number of tumor‐infiltrating CD3+ T cells in recurrent tumors than that in patients with short‐term survival. Furthermore, long‐term surviving patients showed low or undetectable PD‐L1 expression in tumor cells in recurrent GBM biopsies. Conclusion We hypothesise that lack of PD‐L1‐mediated immunosuppression in the TIME may allow efficient immune control following adoptive T‐cell therapy. Future studies combining anti‐PD‐L1 or genetically modified T cells with PD‐1 receptor knockdown could be considered to improve clinical responses in patients who have high PD‐L1 expression in their tumors. |
| first_indexed | 2024-12-13T14:07:56Z |
| format | Article |
| id | doaj.art-1e2763ab58544f1e80a5945763e33a21 |
| institution | Directory Open Access Journal |
| issn | 2050-0068 |
| language | English |
| last_indexed | 2024-12-13T14:07:56Z |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical & Translational Immunology |
| spelling | doaj.art-1e2763ab58544f1e80a5945763e33a212022-12-21T23:42:34ZengWileyClinical & Translational Immunology2050-00682019-01-01811n/an/a10.1002/cti2.1088Impact of pre‐therapy glioblastoma multiforme microenvironment on clinical response to autologous CMV‐specific T‐cell therapyDavid G Walker0Reshma Shakya1Beth Morrison2Michelle A Neller3Katherine K Matthews4John Nicholls5Corey Smith6Rajiv Khanna7Newro Foundation The Wesley Hospital Brisbane QLD AustraliaQIMR Centre for Immunotherapy and Vaccine Development and Tumour Immunology Laboratory QIMR Berghofer Medical Research Institute Brisbane QLD AustraliaNewro Foundation The Wesley Hospital Brisbane QLD AustraliaQIMR Centre for Immunotherapy and Vaccine Development and Tumour Immunology Laboratory QIMR Berghofer Medical Research Institute Brisbane QLD AustraliaQIMR Centre for Immunotherapy and Vaccine Development and Tumour Immunology Laboratory QIMR Berghofer Medical Research Institute Brisbane QLD AustraliaDepartment of Pathology Queen Mary Hospital The University of Hong Kong Hong KongQIMR Centre for Immunotherapy and Vaccine Development and Tumour Immunology Laboratory QIMR Berghofer Medical Research Institute Brisbane QLD AustraliaSchool of Medicine University of Queensland Brisbane QLD AustraliaAbstract Objectives Clinical response to antibody‐based immunotherapies targeting checkpoint inhibitors is critically dependent on the tumor immune microenvironment (TIME). However, the precise impact of the TIME on adoptive cellular immunotherapy remains unexplored. Here we have conducted a long‐term follow‐up analysis of patients with recurrent glioblastoma multiforme (GBM) who were treated with autologous CMV‐specific T‐cell therapy to delineate the potential impact of the TIME on their clinical response. Methods Multiplexed immunohistochemical analysis of CD3, PD‐L1 and Sox‐2 in GBM tissue biopsies obtained before autologous T‐cell therapy was carried out and correlated with long‐term survival of GBM patients adoptively treated with T‐cell therapy. Results Tumor microenvironment analyses revealed that the pre‐treatment cellular composition of the tumor tissue may influence the subsequent response to adoptive T‐cell therapy. GBM patients who showed prolonged overall survival following T‐cell therapy had a significantly lower number of tumor‐infiltrating CD3+ T cells in recurrent tumors than that in patients with short‐term survival. Furthermore, long‐term surviving patients showed low or undetectable PD‐L1 expression in tumor cells in recurrent GBM biopsies. Conclusion We hypothesise that lack of PD‐L1‐mediated immunosuppression in the TIME may allow efficient immune control following adoptive T‐cell therapy. Future studies combining anti‐PD‐L1 or genetically modified T cells with PD‐1 receptor knockdown could be considered to improve clinical responses in patients who have high PD‐L1 expression in their tumors.https://doi.org/10.1002/cti2.1088adoptive immunotherapycytomegalovirus (CMV)glioblastoma multiformetumor microenvironment |
| spellingShingle | David G Walker Reshma Shakya Beth Morrison Michelle A Neller Katherine K Matthews John Nicholls Corey Smith Rajiv Khanna Impact of pre‐therapy glioblastoma multiforme microenvironment on clinical response to autologous CMV‐specific T‐cell therapy Clinical & Translational Immunology adoptive immunotherapy cytomegalovirus (CMV) glioblastoma multiforme tumor microenvironment |
| title | Impact of pre‐therapy glioblastoma multiforme microenvironment on clinical response to autologous CMV‐specific T‐cell therapy |
| title_full | Impact of pre‐therapy glioblastoma multiforme microenvironment on clinical response to autologous CMV‐specific T‐cell therapy |
| title_fullStr | Impact of pre‐therapy glioblastoma multiforme microenvironment on clinical response to autologous CMV‐specific T‐cell therapy |
| title_full_unstemmed | Impact of pre‐therapy glioblastoma multiforme microenvironment on clinical response to autologous CMV‐specific T‐cell therapy |
| title_short | Impact of pre‐therapy glioblastoma multiforme microenvironment on clinical response to autologous CMV‐specific T‐cell therapy |
| title_sort | impact of pre therapy glioblastoma multiforme microenvironment on clinical response to autologous cmv specific t cell therapy |
| topic | adoptive immunotherapy cytomegalovirus (CMV) glioblastoma multiforme tumor microenvironment |
| url | https://doi.org/10.1002/cti2.1088 |
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