Novel TLR2-binding adjuvant induces enhanced T cell responses and tumor eradication
Abstract Background Ligands for the Toll-like receptor (TLR) family can induce activation of cells of the innate immune system and are widely studied for their potential to enhance adaptive immunity. Conjugation of TLR2-ligand Pam3CSK4 to synthetic long peptides (SLPs) was shown to strongly enhance...
Main Authors: | , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMJ Publishing Group
2018-12-01
|
Series: | Journal for ImmunoTherapy of Cancer |
Subjects: | |
Online Access: | http://link.springer.com/article/10.1186/s40425-018-0455-2 |
id |
doaj-709a690ddcf245d583864fadeb597229 |
---|---|
record_format |
Article |
spelling |
doaj-709a690ddcf245d583864fadeb5972292020-11-25T01:14:16ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262018-12-016111310.1186/s40425-018-0455-2Novel TLR2-binding adjuvant induces enhanced T cell responses and tumor eradicationGijs G. Zom0Marian M. J. H. P. Willems1Selina Khan2Tetje C. van der Sluis3Jan Willem Kleinovink4Marcel G. M. Camps5Gijsbert A. van der Marel6Dmitri V. Filippov7Cornelis J. M. Melief8Ferry Ossendorp9Department of Immunohematology and Blood Transfusion, section Tumorimmunology, Leiden University Medical CenterLeiden Institute of Chemistry, Leiden UniversityDepartment of Immunohematology and Blood Transfusion, section Tumorimmunology, Leiden University Medical CenterDepartment of Immunohematology and Blood Transfusion, section Tumorimmunology, Leiden University Medical CenterDepartment of Immunohematology and Blood Transfusion, section Tumorimmunology, Leiden University Medical CenterDepartment of Immunohematology and Blood Transfusion, section Tumorimmunology, Leiden University Medical CenterLeiden Institute of Chemistry, Leiden UniversityLeiden Institute of Chemistry, Leiden UniversityDepartment of Immunohematology and Blood Transfusion, section Tumorimmunology, Leiden University Medical CenterDepartment of Immunohematology and Blood Transfusion, section Tumorimmunology, Leiden University Medical CenterAbstract Background Ligands for the Toll-like receptor (TLR) family can induce activation of cells of the innate immune system and are widely studied for their potential to enhance adaptive immunity. Conjugation of TLR2-ligand Pam3CSK4 to synthetic long peptides (SLPs) was shown to strongly enhance the induction of antitumor immunity. To further improve cancer vaccination, we have previously shown that the novel TLR2-L Amplivant (AV), a modified Pam3CSK4, potentiates the maturation effects on murine DCs. In the current study, we further assessed the immunological properties of AV. Methods Naïve mice were vaccinated with a conjugate of either Pam3CSK4 or AV and an SLP to assess specific T cell priming efficiency in vivo. The potency of AV and Pam3CSK4, either as free compounds or conjugated to different SLPs, to mature murine DCs was compared by stimulating murine dendritic cells overnight followed by ELISA and flow cytometry analysis. Murine tumor experiments were carried out by vaccinating mice carrying established HPV16 E6 and E7-expressing tumors and subsequently analyzing myeloid and lymphoid cells infiltrating the tumor microenvironment. Furthermore, tumor outgrowth after vaccination was monitored to enable comparison of the efficiency to induce antitumor immunity by Pam3CSK-SLP and AV-SLP conjugates. To enhance therapeutic efficacy, AV-SLP conjugate vaccination was combined with ablative therapies to assess whether synergism between such therapies would occur. Results SLPs conjugated to AV induce stronger DC maturation, in vivo T cell priming and antitumor immunity compared to conjugates with Pam3CSK4. Interestingly, AV-SLP conjugates modulate the macrophage populations in the tumor microenvironment, correlating with a therapeutic effect in an aggressive murine tumor model. The potency of AV-SLP conjugates in cancer vaccination operates optimally in combination with chemotherapy or photodynamic therapy. Conclusion These data allow further optimization of vaccination-based immunotherapy of cancer by use of the improved TLR2-ligand Amplivant.http://link.springer.com/article/10.1186/s40425-018-0455-2Toll-like receptor 2AdjuvantCancer vaccinePeptide vaccinationT cell activation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gijs G. Zom Marian M. J. H. P. Willems Selina Khan Tetje C. van der Sluis Jan Willem Kleinovink Marcel G. M. Camps Gijsbert A. van der Marel Dmitri V. Filippov Cornelis J. M. Melief Ferry Ossendorp |
spellingShingle |
Gijs G. Zom Marian M. J. H. P. Willems Selina Khan Tetje C. van der Sluis Jan Willem Kleinovink Marcel G. M. Camps Gijsbert A. van der Marel Dmitri V. Filippov Cornelis J. M. Melief Ferry Ossendorp Novel TLR2-binding adjuvant induces enhanced T cell responses and tumor eradication Journal for ImmunoTherapy of Cancer Toll-like receptor 2 Adjuvant Cancer vaccine Peptide vaccination T cell activation |
author_facet |
Gijs G. Zom Marian M. J. H. P. Willems Selina Khan Tetje C. van der Sluis Jan Willem Kleinovink Marcel G. M. Camps Gijsbert A. van der Marel Dmitri V. Filippov Cornelis J. M. Melief Ferry Ossendorp |
author_sort |
Gijs G. Zom |
title |
Novel TLR2-binding adjuvant induces enhanced T cell responses and tumor eradication |
title_short |
Novel TLR2-binding adjuvant induces enhanced T cell responses and tumor eradication |
title_full |
Novel TLR2-binding adjuvant induces enhanced T cell responses and tumor eradication |
title_fullStr |
Novel TLR2-binding adjuvant induces enhanced T cell responses and tumor eradication |
title_full_unstemmed |
Novel TLR2-binding adjuvant induces enhanced T cell responses and tumor eradication |
title_sort |
novel tlr2-binding adjuvant induces enhanced t cell responses and tumor eradication |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2018-12-01 |
description |
Abstract Background Ligands for the Toll-like receptor (TLR) family can induce activation of cells of the innate immune system and are widely studied for their potential to enhance adaptive immunity. Conjugation of TLR2-ligand Pam3CSK4 to synthetic long peptides (SLPs) was shown to strongly enhance the induction of antitumor immunity. To further improve cancer vaccination, we have previously shown that the novel TLR2-L Amplivant (AV), a modified Pam3CSK4, potentiates the maturation effects on murine DCs. In the current study, we further assessed the immunological properties of AV. Methods Naïve mice were vaccinated with a conjugate of either Pam3CSK4 or AV and an SLP to assess specific T cell priming efficiency in vivo. The potency of AV and Pam3CSK4, either as free compounds or conjugated to different SLPs, to mature murine DCs was compared by stimulating murine dendritic cells overnight followed by ELISA and flow cytometry analysis. Murine tumor experiments were carried out by vaccinating mice carrying established HPV16 E6 and E7-expressing tumors and subsequently analyzing myeloid and lymphoid cells infiltrating the tumor microenvironment. Furthermore, tumor outgrowth after vaccination was monitored to enable comparison of the efficiency to induce antitumor immunity by Pam3CSK-SLP and AV-SLP conjugates. To enhance therapeutic efficacy, AV-SLP conjugate vaccination was combined with ablative therapies to assess whether synergism between such therapies would occur. Results SLPs conjugated to AV induce stronger DC maturation, in vivo T cell priming and antitumor immunity compared to conjugates with Pam3CSK4. Interestingly, AV-SLP conjugates modulate the macrophage populations in the tumor microenvironment, correlating with a therapeutic effect in an aggressive murine tumor model. The potency of AV-SLP conjugates in cancer vaccination operates optimally in combination with chemotherapy or photodynamic therapy. Conclusion These data allow further optimization of vaccination-based immunotherapy of cancer by use of the improved TLR2-ligand Amplivant. |
topic |
Toll-like receptor 2 Adjuvant Cancer vaccine Peptide vaccination T cell activation |
url |
http://link.springer.com/article/10.1186/s40425-018-0455-2 |
work_keys_str_mv |
AT gijsgzom noveltlr2bindingadjuvantinducesenhancedtcellresponsesandtumoreradication AT marianmjhpwillems noveltlr2bindingadjuvantinducesenhancedtcellresponsesandtumoreradication AT selinakhan noveltlr2bindingadjuvantinducesenhancedtcellresponsesandtumoreradication AT tetjecvandersluis noveltlr2bindingadjuvantinducesenhancedtcellresponsesandtumoreradication AT janwillemkleinovink noveltlr2bindingadjuvantinducesenhancedtcellresponsesandtumoreradication AT marcelgmcamps noveltlr2bindingadjuvantinducesenhancedtcellresponsesandtumoreradication AT gijsbertavandermarel noveltlr2bindingadjuvantinducesenhancedtcellresponsesandtumoreradication AT dmitrivfilippov noveltlr2bindingadjuvantinducesenhancedtcellresponsesandtumoreradication AT cornelisjmmelief noveltlr2bindingadjuvantinducesenhancedtcellresponsesandtumoreradication AT ferryossendorp noveltlr2bindingadjuvantinducesenhancedtcellresponsesandtumoreradication |
_version_ |
1725157787551399936 |