Oncolytic Orf virus licenses NK cells via cDC1 to activate innate and adaptive antitumor mechanisms and extends survival in a murine model of late-stage ovarian cancer
Background Novel therapies are needed to improve outcomes for women diagnosed with ovarian cancer. Oncolytic viruses are multifunctional immunotherapeutic biologics that preferentially infect cancer cells and stimulate inflammation with the potential to generate antitumor immunity. Herein we describ...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2022-03-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e004335.full |
| _version_ | 1797771674309885952 |
|---|---|
| author | Jacob P van Vloten Kathy Matuszewska Mark A A Minow Jessica A Minott Lisa A Santry Madison Pereira Ashley A Stegelmeier Thomas M McAusland Elaine M Klafuric Khalil Karimi Joseph Colasanti D Grant McFadden James J Petrik Byram W Bridle Sarah K Wootton |
| author_facet | Jacob P van Vloten Kathy Matuszewska Mark A A Minow Jessica A Minott Lisa A Santry Madison Pereira Ashley A Stegelmeier Thomas M McAusland Elaine M Klafuric Khalil Karimi Joseph Colasanti D Grant McFadden James J Petrik Byram W Bridle Sarah K Wootton |
| author_sort | Jacob P van Vloten |
| collection | DOAJ |
| description | Background Novel therapies are needed to improve outcomes for women diagnosed with ovarian cancer. Oncolytic viruses are multifunctional immunotherapeutic biologics that preferentially infect cancer cells and stimulate inflammation with the potential to generate antitumor immunity. Herein we describe Parapoxvirus ovis (Orf virus (OrfV)), an oncolytic poxvirus, as a viral immunotherapy for ovarian cancer.Methods The immunotherapeutic potential of OrfV was tested in the ID8 orthotopic mouse model of end-stage epithelial ovarian carcinoma. Immune cell profiling, impact on secondary lesion development and survival were evaluated in OrfV-treated mice as well as in Batf3 knockout, mice depleted of specific immune cell subsets and in mice where the primary tumor was removed. Finally, we interrogated gene expression datasets from primary human ovarian tumors from the International Cancer Genome Consortium database to determine whether the interplay we observed between natural killer (NK) cells, classical type 1 dendritic cells (cDC1s) and T cells exists and influences outcomes in human ovarian cancer.Results OrfV was an effective monotherapy in a murine model of advanced-stage epithelial ovarian cancer. OrfV intervention relied on NK cells, which when depleted abrogated antitumor CD8+ T-cell responses. OrfV therapy was shown to require cDC1s in experiments with BATF3 knockout mice, which do not have mature cDC1s. Furthermore, cDC1s governed antitumor NK and T-cell responses to mediate antitumor efficacy following OrfV. Primary tumor removal, a common treatment option in human patients, was effectively combined with OrfV for optimal therapeutic outcome. Analysis of human RNA sequencing datasets revealed that cDC1s correlate with NK cells in human ovarian cancer and that intratumoral NK cells correlate positively with survival.Conclusions The data herein support the translational potential of OrfV as an NK stimulating immunotherapeutic for the treatment of advanced-stage ovarian cancer. |
| first_indexed | 2024-03-12T21:41:00Z |
| format | Article |
| id | doaj.art-042f07917dda4af9ab08f790da95d074 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T21:41:00Z |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-042f07917dda4af9ab08f790da95d0742023-07-26T22:55:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-004335Oncolytic Orf virus licenses NK cells via cDC1 to activate innate and adaptive antitumor mechanisms and extends survival in a murine model of late-stage ovarian cancerJacob P van Vloten0Kathy Matuszewska1Mark A A Minow2Jessica A Minott3Lisa A Santry4Madison Pereira5Ashley A Stegelmeier6Thomas M McAusland7Elaine M Klafuric8Khalil Karimi9Joseph Colasanti10D Grant McFadden11James J Petrik12Byram W Bridle13Sarah K Wootton14Department of Pathobiology, University of Guelph, Guelph, Ontario, CanadaDepartment of Biomedical Sciences, University of Guelph, Guelph, Ontario, CanadaMolecular and Cellular Biology, University of Guelph, Guelph, Ontario, CanadaDepartment of Pathobiology, University of Guelph, Guelph, Ontario, CanadaDepartment of Pathobiology, University of Guelph, Guelph, Ontario, CanadaDepartment of Biomedical Sciences, University of Guelph, Guelph, Ontario, CanadaDepartment of Pathobiology, University of Guelph, Guelph, Ontario, CanadaDepartment of Pathobiology, University of Guelph, Guelph, Ontario, CanadaDepartment of Pathobiology, University of Guelph, Guelph, Ontario, CanadaDepartment of Pathobiology, University of Guelph, Guelph, Ontario, CanadaDepartment of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, CanadaBiodesign Institute, Arizona State University, Tempe, Arizona, USADepartment of Biomedical Sciences, University of Guelph, Guelph, Ontario, CanadaDepartment of Pathobiology, University of Guelph, Guelph, Ontario, CanadaDepartment of Pathobiology, University of Guelph, Guelph, Ontario, CanadaBackground Novel therapies are needed to improve outcomes for women diagnosed with ovarian cancer. Oncolytic viruses are multifunctional immunotherapeutic biologics that preferentially infect cancer cells and stimulate inflammation with the potential to generate antitumor immunity. Herein we describe Parapoxvirus ovis (Orf virus (OrfV)), an oncolytic poxvirus, as a viral immunotherapy for ovarian cancer.Methods The immunotherapeutic potential of OrfV was tested in the ID8 orthotopic mouse model of end-stage epithelial ovarian carcinoma. Immune cell profiling, impact on secondary lesion development and survival were evaluated in OrfV-treated mice as well as in Batf3 knockout, mice depleted of specific immune cell subsets and in mice where the primary tumor was removed. Finally, we interrogated gene expression datasets from primary human ovarian tumors from the International Cancer Genome Consortium database to determine whether the interplay we observed between natural killer (NK) cells, classical type 1 dendritic cells (cDC1s) and T cells exists and influences outcomes in human ovarian cancer.Results OrfV was an effective monotherapy in a murine model of advanced-stage epithelial ovarian cancer. OrfV intervention relied on NK cells, which when depleted abrogated antitumor CD8+ T-cell responses. OrfV therapy was shown to require cDC1s in experiments with BATF3 knockout mice, which do not have mature cDC1s. Furthermore, cDC1s governed antitumor NK and T-cell responses to mediate antitumor efficacy following OrfV. Primary tumor removal, a common treatment option in human patients, was effectively combined with OrfV for optimal therapeutic outcome. Analysis of human RNA sequencing datasets revealed that cDC1s correlate with NK cells in human ovarian cancer and that intratumoral NK cells correlate positively with survival.Conclusions The data herein support the translational potential of OrfV as an NK stimulating immunotherapeutic for the treatment of advanced-stage ovarian cancer.https://jitc.bmj.com/content/10/3/e004335.full |
| spellingShingle | Jacob P van Vloten Kathy Matuszewska Mark A A Minow Jessica A Minott Lisa A Santry Madison Pereira Ashley A Stegelmeier Thomas M McAusland Elaine M Klafuric Khalil Karimi Joseph Colasanti D Grant McFadden James J Petrik Byram W Bridle Sarah K Wootton Oncolytic Orf virus licenses NK cells via cDC1 to activate innate and adaptive antitumor mechanisms and extends survival in a murine model of late-stage ovarian cancer Journal for ImmunoTherapy of Cancer |
| title | Oncolytic Orf virus licenses NK cells via cDC1 to activate innate and adaptive antitumor mechanisms and extends survival in a murine model of late-stage ovarian cancer |
| title_full | Oncolytic Orf virus licenses NK cells via cDC1 to activate innate and adaptive antitumor mechanisms and extends survival in a murine model of late-stage ovarian cancer |
| title_fullStr | Oncolytic Orf virus licenses NK cells via cDC1 to activate innate and adaptive antitumor mechanisms and extends survival in a murine model of late-stage ovarian cancer |
| title_full_unstemmed | Oncolytic Orf virus licenses NK cells via cDC1 to activate innate and adaptive antitumor mechanisms and extends survival in a murine model of late-stage ovarian cancer |
| title_short | Oncolytic Orf virus licenses NK cells via cDC1 to activate innate and adaptive antitumor mechanisms and extends survival in a murine model of late-stage ovarian cancer |
| title_sort | oncolytic orf virus licenses nk cells via cdc1 to activate innate and adaptive antitumor mechanisms and extends survival in a murine model of late stage ovarian cancer |
| url | https://jitc.bmj.com/content/10/3/e004335.full |
| work_keys_str_mv | AT jacobpvanvloten oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT kathymatuszewska oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT markaaminow oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT jessicaaminott oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT lisaasantry oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT madisonpereira oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT ashleyastegelmeier oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT thomasmmcausland oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT elainemklafuric oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT khalilkarimi oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT josephcolasanti oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT dgrantmcfadden oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT jamesjpetrik oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT byramwbridle oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer AT sarahkwootton oncolyticorfviruslicensesnkcellsviacdc1toactivateinnateandadaptiveantitumormechanismsandextendssurvivalinamurinemodeloflatestageovariancancer |