Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy
Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease, with a survival rate of ~12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted the outcomes in patients with...
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BMJ Publishing Group
2024-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/1/e008086.full |
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| author | Gregory B. Lesinski Chrystal M. Paulos Maggie Phillips Jacklyn Hammons Isaac Karpovsky Zaid Mahdi Natalie K. Horvat Megan M. Wyatt Margaret A. Hall Cameron J. Herting Richard A. Moffitt |
| author_facet | Gregory B. Lesinski Chrystal M. Paulos Maggie Phillips Jacklyn Hammons Isaac Karpovsky Zaid Mahdi Natalie K. Horvat Megan M. Wyatt Margaret A. Hall Cameron J. Herting Richard A. Moffitt |
| author_sort | Gregory B. Lesinski |
| collection | DOAJ |
| description | Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease, with a survival rate of ~12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted the outcomes in patients with PDAC, due in part to the hostile tumor microenvironment (TME) which limits T cell trafficking and persistence. We posit that murine models serve as useful tools to study the fate of T cell therapy. Currently, genetically engineered mouse models (GEMMs) for PDAC are considered a “gold-standard” as they recapitulate many aspects of human disease. However, these models have limitations, including marked tumor variability across individual mice and the cost of colony maintenance.Methods Using flow cytometry and immunohistochemistry, we characterized the immunological features and trafficking patterns of adoptively transferred T cells in orthotopic PDAC (C57BL/6) models using two mouse cell lines, KPC-Luc and MT-5, isolated from C57BL/6 KPC-GEMM (KrasLSL-G12D/+p53−/− and KrasLSL-G12D/+p53LSL-R172H/+, respectively).Results The MT-5 orthotopic model best recapitulates the cellular and stromal features of the TME in the PDAC GEMM. In contrast, far more host immune cells infiltrate the KPC-Luc tumors, which have less stroma, although CD4+ and CD8+ T cells were similarly detected in the MT-5 tumors compared with KPC-GEMM in mice. Interestingly, we found that chimeric antigen receptor (CAR) T cells redirected to recognize mesothelin on these tumors that signal via CD3ζ and 41BB (Meso-41BBζ-CAR T cells) infiltrated the tumors of mice bearing stroma-devoid KPC-Luc orthotopic tumors, but not MT-5 tumors.Conclusions Our data establish for the first time a reproducible and realistic clinical system useful for modeling stroma-rich and stroma-devoid PDAC tumors. These models shall serve an indepth study of how to overcome barriers that limit antitumor activity of adoptively transferred T cells. |
| format | Article |
| id | doaj-art-ccc1774c4aff426fb03919b5256d20ee |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-ccc1774c4aff426fb03919b5256d20ee2025-02-02T17:05:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-01-0112110.1136/jitc-2023-008086Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapyGregory B. Lesinski0Chrystal M. Paulos1Maggie Phillips2Jacklyn Hammons3Isaac Karpovsky4Zaid Mahdi5Natalie K. Horvat6Megan M. Wyatt7Margaret A. Hall8Cameron J. Herting9Richard A. Moffitt10Aff98 grid.261331.40000000122857943The Ohio State University Columbus OH USAAff15 0000 0001 2189 3475grid.259828.cDepartment of Microbiology and Immunology Hollings Cancer CenterMedical University of South Carolina (MUSC) Charleston South Carolina USADepartment of Hematology and Oncology, Emory University, Atlanta, Georgia, USAEmory University, Atlanta, GA, USAEmory University, Atlanta, GA, USAEmory University, Atlanta, GA, USADepartment of Pediatric Hematology, Oncology and Immunology, Emory University, Atlanta, Georgia, USADepartment of Surgery, Department of Microbiology & Immunology, Emory University Winship Cancer Institute, Atlanta, Georgia, USADepartment of Hematology and Oncology, Emory University, Atlanta, Georgia, USADepartment of Hematology and Oncology, Emory University, Atlanta, Georgia, USADepartment of Hematology and Oncology, Emory University, Atlanta, Georgia, USABackground Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease, with a survival rate of ~12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted the outcomes in patients with PDAC, due in part to the hostile tumor microenvironment (TME) which limits T cell trafficking and persistence. We posit that murine models serve as useful tools to study the fate of T cell therapy. Currently, genetically engineered mouse models (GEMMs) for PDAC are considered a “gold-standard” as they recapitulate many aspects of human disease. However, these models have limitations, including marked tumor variability across individual mice and the cost of colony maintenance.Methods Using flow cytometry and immunohistochemistry, we characterized the immunological features and trafficking patterns of adoptively transferred T cells in orthotopic PDAC (C57BL/6) models using two mouse cell lines, KPC-Luc and MT-5, isolated from C57BL/6 KPC-GEMM (KrasLSL-G12D/+p53−/− and KrasLSL-G12D/+p53LSL-R172H/+, respectively).Results The MT-5 orthotopic model best recapitulates the cellular and stromal features of the TME in the PDAC GEMM. In contrast, far more host immune cells infiltrate the KPC-Luc tumors, which have less stroma, although CD4+ and CD8+ T cells were similarly detected in the MT-5 tumors compared with KPC-GEMM in mice. Interestingly, we found that chimeric antigen receptor (CAR) T cells redirected to recognize mesothelin on these tumors that signal via CD3ζ and 41BB (Meso-41BBζ-CAR T cells) infiltrated the tumors of mice bearing stroma-devoid KPC-Luc orthotopic tumors, but not MT-5 tumors.Conclusions Our data establish for the first time a reproducible and realistic clinical system useful for modeling stroma-rich and stroma-devoid PDAC tumors. These models shall serve an indepth study of how to overcome barriers that limit antitumor activity of adoptively transferred T cells.https://jitc.bmj.com/content/12/1/e008086.full |
| spellingShingle | Gregory B. Lesinski Chrystal M. Paulos Maggie Phillips Jacklyn Hammons Isaac Karpovsky Zaid Mahdi Natalie K. Horvat Megan M. Wyatt Margaret A. Hall Cameron J. Herting Richard A. Moffitt Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy Journal for ImmunoTherapy of Cancer |
| title | Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy |
| title_full | Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy |
| title_fullStr | Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy |
| title_full_unstemmed | Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy |
| title_short | Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy |
| title_sort | clinically relevant orthotopic pancreatic cancer models for adoptive t cell transfer therapy |
| url | https://jitc.bmj.com/content/12/1/e008086.full |
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