Tbet and IL-36γ cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment
We have previously reported that direct injection of dendritic cells (DC) engineered to express the Type-1 transactivator Tbet (i.e., DC.Tbet) into murine tumors results in antitumor efficacy in association with the development of structures resembling tertiary lymphoid organs (TLO) in the tumor mic...
Main Authors: | , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Taylor & Francis Group
2017-06-01
|
Series: | OncoImmunology |
Subjects: | |
Online Access: | http://dx.doi.org/10.1080/2162402X.2017.1322238 |
id |
doaj-ae1cf937d236486eb5995d5b55f30a66 |
---|---|
record_format |
Article |
spelling |
doaj-ae1cf937d236486eb5995d5b55f30a662020-11-25T03:01:12ZengTaylor & Francis GroupOncoImmunology2162-402X2017-06-016610.1080/2162402X.2017.13222381322238Tbet and IL-36γ cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironmentAliyah M. Weinstein0Lu Chen1Emily A. Brzana2Prashanti R. Patil3Jennifer L. Taylor4Kellsye L. Fabian5Callen T. Wallace6Sabrina D. Jones7Simon C. Watkins8Binfeng Lu9David F. Stroncek10Timothy L. Denning11Yang-Xin Fu12Peter A. Cohen13Walter J. Storkus14University of Pittsburgh School of Medicine (UPSOM)University of Pittsburgh School of Medicine (UPSOM)UPSOMUPSOMUPSOMUniversity of Pittsburgh School of Medicine (UPSOM)UPSOMUPSOMUPSOMUniversity of Pittsburgh School of Medicine (UPSOM)Clinical Center, NIHCenter for Inflammation, Immunity & Infection at Georgia State UniversityUT Southwestern Medical CenterMayo ClinicUniversity of Pittsburgh School of Medicine (UPSOM)We have previously reported that direct injection of dendritic cells (DC) engineered to express the Type-1 transactivator Tbet (i.e., DC.Tbet) into murine tumors results in antitumor efficacy in association with the development of structures resembling tertiary lymphoid organs (TLO) in the tumor microenvironment (TME). These TLO contained robust infiltrates of B cells, DC, NK cells, and T cells in proximity to PNAd+ blood vessels; however, they were considered incomplete, since the recruited B cells failed to organize into classic germinal center-like structures. We now report that antitumor efficacy and TLO-inducing capacity of DC.Tbet-based i.t. therapy is operational in peripheral lymph node-deficient LTA−/− mice, and that it is highly dependent upon a direct Tbet target gene product, IL-36γ/IL-1F9. Intratumoral DC.Tbet fails to provide protection to tumor-bearing IL-36R−/− hosts, or to tumor-bearing wild-type recipient mice co-administered rmIL-1F5/IL-36RN, a natural IL-36R antagonist. Remarkably, the injection of tumors with DC engineered to secrete a bioactive form of mIL-36γ (DC.IL36γ) also initiated therapeutic TLO and slowed tumor progression in vivo. Furthermore, DC.IL36γ cells strongly upregulated their expression of Tbet, suggesting that Tbet and IL-36γ cooperate to reinforce each other's expression in DC, rendering them competent to promote TLO formation in an “immunologically normalized,” therapeutic TME.http://dx.doi.org/10.1080/2162402X.2017.1322238dendritic cellsimmunotherapyinterleukin (il)-36γtbettertiary lymphoid organtumor |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Aliyah M. Weinstein Lu Chen Emily A. Brzana Prashanti R. Patil Jennifer L. Taylor Kellsye L. Fabian Callen T. Wallace Sabrina D. Jones Simon C. Watkins Binfeng Lu David F. Stroncek Timothy L. Denning Yang-Xin Fu Peter A. Cohen Walter J. Storkus |
spellingShingle |
Aliyah M. Weinstein Lu Chen Emily A. Brzana Prashanti R. Patil Jennifer L. Taylor Kellsye L. Fabian Callen T. Wallace Sabrina D. Jones Simon C. Watkins Binfeng Lu David F. Stroncek Timothy L. Denning Yang-Xin Fu Peter A. Cohen Walter J. Storkus Tbet and IL-36γ cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment OncoImmunology dendritic cells immunotherapy interleukin (il)-36γ tbet tertiary lymphoid organ tumor |
author_facet |
Aliyah M. Weinstein Lu Chen Emily A. Brzana Prashanti R. Patil Jennifer L. Taylor Kellsye L. Fabian Callen T. Wallace Sabrina D. Jones Simon C. Watkins Binfeng Lu David F. Stroncek Timothy L. Denning Yang-Xin Fu Peter A. Cohen Walter J. Storkus |
author_sort |
Aliyah M. Weinstein |
title |
Tbet and IL-36γ cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment |
title_short |
Tbet and IL-36γ cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment |
title_full |
Tbet and IL-36γ cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment |
title_fullStr |
Tbet and IL-36γ cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment |
title_full_unstemmed |
Tbet and IL-36γ cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment |
title_sort |
tbet and il-36γ cooperate in therapeutic dc-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment |
publisher |
Taylor & Francis Group |
series |
OncoImmunology |
issn |
2162-402X |
publishDate |
2017-06-01 |
description |
We have previously reported that direct injection of dendritic cells (DC) engineered to express the Type-1 transactivator Tbet (i.e., DC.Tbet) into murine tumors results in antitumor efficacy in association with the development of structures resembling tertiary lymphoid organs (TLO) in the tumor microenvironment (TME). These TLO contained robust infiltrates of B cells, DC, NK cells, and T cells in proximity to PNAd+ blood vessels; however, they were considered incomplete, since the recruited B cells failed to organize into classic germinal center-like structures. We now report that antitumor efficacy and TLO-inducing capacity of DC.Tbet-based i.t. therapy is operational in peripheral lymph node-deficient LTA−/− mice, and that it is highly dependent upon a direct Tbet target gene product, IL-36γ/IL-1F9. Intratumoral DC.Tbet fails to provide protection to tumor-bearing IL-36R−/− hosts, or to tumor-bearing wild-type recipient mice co-administered rmIL-1F5/IL-36RN, a natural IL-36R antagonist. Remarkably, the injection of tumors with DC engineered to secrete a bioactive form of mIL-36γ (DC.IL36γ) also initiated therapeutic TLO and slowed tumor progression in vivo. Furthermore, DC.IL36γ cells strongly upregulated their expression of Tbet, suggesting that Tbet and IL-36γ cooperate to reinforce each other's expression in DC, rendering them competent to promote TLO formation in an “immunologically normalized,” therapeutic TME. |
topic |
dendritic cells immunotherapy interleukin (il)-36γ tbet tertiary lymphoid organ tumor |
url |
http://dx.doi.org/10.1080/2162402X.2017.1322238 |
work_keys_str_mv |
AT aliyahmweinstein tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT luchen tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT emilyabrzana tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT prashantirpatil tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT jenniferltaylor tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT kellsyelfabian tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT callentwallace tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT sabrinadjones tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT simoncwatkins tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT binfenglu tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT davidfstroncek tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT timothyldenning tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT yangxinfu tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT peteracohen tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment AT walterjstorkus tbetandil36gcooperateintherapeuticdcmediatedpromotionofectopiclymphoidorganogenesisinthetumormicroenvironment |
_version_ |
1724694435278618624 |