Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils
Background Antitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-04-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/4/e006463.full |
| _version_ | 1827964559145566208 |
|---|---|
| author | Daniel Landi Annick Desjardins Matthias Gromeier Darell D Bigner Smita K Nair Michael C Brown Georgia M Beasley David M Ashley Yuanfan Yang Zachary P McKay Dina M Randazzo |
| author_facet | Daniel Landi Annick Desjardins Matthias Gromeier Darell D Bigner Smita K Nair Michael C Brown Georgia M Beasley David M Ashley Yuanfan Yang Zachary P McKay Dina M Randazzo |
| author_sort | Daniel Landi |
| collection | DOAJ |
| description | Background Antitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy.Methods The impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8+ T-cell and B-cell knockout, CD4+ T-cell depletion, CD4+ T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans.Results Prior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4+ T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8+ T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy.Conclusion Pre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T-cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells. |
| first_indexed | 2024-04-09T17:18:24Z |
| format | Article |
| id | doaj.art-73dcacec3cd343d394456d6088d99ca1 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-09T17:18:24Z |
| publishDate | 2023-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-73dcacec3cd343d394456d6088d99ca12023-04-19T08:30:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-04-0111410.1136/jitc-2022-006463Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophilsDaniel Landi0Annick Desjardins1Matthias Gromeier2Darell D Bigner3Smita K Nair4Michael C Brown5Georgia M Beasley6David M Ashley7Yuanfan Yang8Zachary P McKay9Dina M Randazzo10ǘ landi@bcm.eduAff1 0000000100241216grid.189509.cDepartment of Neurosurgery and the Preston Robert Tisch Brain Tumor CenterDuke University Medical Center Box 3156 Medical Sciences Research Building, Rm 181c 27710 Durham NC USADepartment of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USADepartment of Medicine, Duke University, Durham, North Carolina, USADepartment of Surgery, Duke University School of Medicine, Durham, North Carolina, USAAff1 grid.26009.3d0000000419367961Duke University Durham NC USA2 Duke Cancer Institute, Duke University, Durham, NC, USADuke Cancer Institute, Duke University, Durham, North Carolina, USADuke University, Durham, United StatesDepartment of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USADepartment of Neurosurgery, Duke University School of Medicine, Durham, North Carolina, USABackground Antitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy.Methods The impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8+ T-cell and B-cell knockout, CD4+ T-cell depletion, CD4+ T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans.Results Prior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4+ T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8+ T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy.Conclusion Pre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T-cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells.https://jitc.bmj.com/content/11/4/e006463.full |
| spellingShingle | Daniel Landi Annick Desjardins Matthias Gromeier Darell D Bigner Smita K Nair Michael C Brown Georgia M Beasley David M Ashley Yuanfan Yang Zachary P McKay Dina M Randazzo Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils Journal for ImmunoTherapy of Cancer |
| title | Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils |
| title_full | Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils |
| title_fullStr | Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils |
| title_full_unstemmed | Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils |
| title_short | Intratumor childhood vaccine-specific CD4+ T-cell recall coordinates antitumor CD8+ T cells and eosinophils |
| title_sort | intratumor childhood vaccine specific cd4 t cell recall coordinates antitumor cd8 t cells and eosinophils |
| url | https://jitc.bmj.com/content/11/4/e006463.full |
| work_keys_str_mv | AT daniellandi intratumorchildhoodvaccinespecificcd4tcellrecallcoordinatesantitumorcd8tcellsandeosinophils AT annickdesjardins intratumorchildhoodvaccinespecificcd4tcellrecallcoordinatesantitumorcd8tcellsandeosinophils AT matthiasgromeier intratumorchildhoodvaccinespecificcd4tcellrecallcoordinatesantitumorcd8tcellsandeosinophils AT darelldbigner intratumorchildhoodvaccinespecificcd4tcellrecallcoordinatesantitumorcd8tcellsandeosinophils AT smitaknair intratumorchildhoodvaccinespecificcd4tcellrecallcoordinatesantitumorcd8tcellsandeosinophils AT michaelcbrown intratumorchildhoodvaccinespecificcd4tcellrecallcoordinatesantitumorcd8tcellsandeosinophils AT georgiambeasley intratumorchildhoodvaccinespecificcd4tcellrecallcoordinatesantitumorcd8tcellsandeosinophils AT davidmashley intratumorchildhoodvaccinespecificcd4tcellrecallcoordinatesantitumorcd8tcellsandeosinophils AT yuanfanyang intratumorchildhoodvaccinespecificcd4tcellrecallcoordinatesantitumorcd8tcellsandeosinophils AT zacharypmckay intratumorchildhoodvaccinespecificcd4tcellrecallcoordinatesantitumorcd8tcellsandeosinophils AT dinamrandazzo intratumorchildhoodvaccinespecificcd4tcellrecallcoordinatesantitumorcd8tcellsandeosinophils |