Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment
Background Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vrsus progression remain poorly understood. However, to date there are few preclinical models that accurately represent these disparate disease scen...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2025-01-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/1/e010405.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832540958846091264 |
|---|---|
| author | Christian Klein Maria Amann Jacob Gadwa Laurel B Darragh Miles Piper Diemmy Nguyen Sana D Karam Michael W Knitz Justin Yu Nicholas Olimpo Sophia Corbo Jessica I Beynor Brooke Neupert Alexander T Nguyen Chloe Hodgson Khalid NM Abdelazeem Anthony Saviola Laurene Pousse Ali Bransi Mudita Pincha |
| author_facet | Christian Klein Maria Amann Jacob Gadwa Laurel B Darragh Miles Piper Diemmy Nguyen Sana D Karam Michael W Knitz Justin Yu Nicholas Olimpo Sophia Corbo Jessica I Beynor Brooke Neupert Alexander T Nguyen Chloe Hodgson Khalid NM Abdelazeem Anthony Saviola Laurene Pousse Ali Bransi Mudita Pincha |
| author_sort | Christian Klein |
| collection | DOAJ |
| description | Background Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vrsus progression remain poorly understood. However, to date there are few preclinical models that accurately represent these disparate disease scenarios.Methods Using combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2Rβγ biased signaling, and OX40 agonism we were able to generate preclinical tumor models with conflicting responses, where head and neck squamous cell carcinoma (HNSCC) models respond and pancreatic ductal adenocarcinoma (PDAC) progresses.Results By modeling these disparate states, we find that regulatory T cells (Tregs) are expanded in PDAC tumors undergoing treatment, constraining tumor reactive CD8 T cell activity. Consequently, the depletion of Tregs restores the therapeutic efficacy of our treatment and abrogates the disparity between models. Moreover, we show that through heterotopic implantations the site of tumor development defines the response to therapy, as implantation of HNSCC tumors into the pancreas resulted in comparable levels of tumor progression.Conclusions This work highlights the complexity of combining immunotherapies within the tumor microenvironment (TME) and further defines the immune and non-immune components of the TME as an intrinsic feature of immune suppression. |
| format | Article |
| id | doaj-art-7be4674ac8d84015ba0b222b6faf046d |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-7be4674ac8d84015ba0b222b6faf046d2025-02-04T11:00:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-01-0113110.1136/jitc-2024-010405Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironmentChristian Klein0Maria Amann1Jacob Gadwa2Laurel B Darragh3Miles Piper4Diemmy Nguyen5Sana D Karam6Michael W Knitz7Justin Yu8Nicholas Olimpo9Sophia Corbo10Jessica I Beynor11Brooke Neupert12Alexander T Nguyen13Chloe Hodgson14Khalid NM Abdelazeem15Anthony Saviola16Laurene Pousse17Ali Bransi18Mudita Pincha19Roche Innovation Centre Zurich, Schlieren, SwitzerlandRoche Innovation Centre Zurich, Schlieren, SwitzerlandDepartment of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USADepartment of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USADepartment of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USADepartment of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Otolaryngology - Head & Neck Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USADepartment of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USADepartment of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USADepartment of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USADepartment of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USADepartment of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USADepartment of Radiation Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USADepartment of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USARoche Innovation Centre Zurich, Schlieren, SwitzerlandRoche Innovation Centre Zurich, Schlieren, SwitzerlandRoche Innovation Centre Zurich, Schlieren, SwitzerlandBackground Treatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vrsus progression remain poorly understood. However, to date there are few preclinical models that accurately represent these disparate disease scenarios.Methods Using combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2Rβγ biased signaling, and OX40 agonism we were able to generate preclinical tumor models with conflicting responses, where head and neck squamous cell carcinoma (HNSCC) models respond and pancreatic ductal adenocarcinoma (PDAC) progresses.Results By modeling these disparate states, we find that regulatory T cells (Tregs) are expanded in PDAC tumors undergoing treatment, constraining tumor reactive CD8 T cell activity. Consequently, the depletion of Tregs restores the therapeutic efficacy of our treatment and abrogates the disparity between models. Moreover, we show that through heterotopic implantations the site of tumor development defines the response to therapy, as implantation of HNSCC tumors into the pancreas resulted in comparable levels of tumor progression.Conclusions This work highlights the complexity of combining immunotherapies within the tumor microenvironment (TME) and further defines the immune and non-immune components of the TME as an intrinsic feature of immune suppression.https://jitc.bmj.com/content/13/1/e010405.full |
| spellingShingle | Christian Klein Maria Amann Jacob Gadwa Laurel B Darragh Miles Piper Diemmy Nguyen Sana D Karam Michael W Knitz Justin Yu Nicholas Olimpo Sophia Corbo Jessica I Beynor Brooke Neupert Alexander T Nguyen Chloe Hodgson Khalid NM Abdelazeem Anthony Saviola Laurene Pousse Ali Bransi Mudita Pincha Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment Journal for ImmunoTherapy of Cancer |
| title | Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment |
| title_full | Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment |
| title_fullStr | Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment |
| title_full_unstemmed | Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment |
| title_short | Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment |
| title_sort | divergent response to radio immunotherapy is defined by intrinsic features of the tumor microenvironment |
| url | https://jitc.bmj.com/content/13/1/e010405.full |
| work_keys_str_mv | AT christianklein divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT mariaamann divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT jacobgadwa divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT laurelbdarragh divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT milespiper divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT diemmynguyen divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT sanadkaram divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT michaelwknitz divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT justinyu divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT nicholasolimpo divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT sophiacorbo divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT jessicaibeynor divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT brookeneupert divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT alexandertnguyen divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT chloehodgson divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT khalidnmabdelazeem divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT anthonysaviola divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT laurenepousse divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT alibransi divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment AT muditapincha divergentresponsetoradioimmunotherapyisdefinedbyintrinsicfeaturesofthetumormicroenvironment |