Abstract:
: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.
journal_name
Oncoimmunologyjournal_title
Oncoimmunologyauthors
Weinstein AM,Chen L,Brzana EA,Patil PR,Taylor JL,Fabian KL,Wallace CT,Jones SD,Watkins SC,Lu B,Stroncek DF,Denning TL,Fu YX,Cohen PA,Storkus WJdoi
10.1080/2162402X.2017.1322238subject
Has Abstractpub_date
2017-04-28 00:00:00pages
e1322238issue
6eissn
2162-4011issn
2162-402Xpii
1322238journal_volume
6pub_type
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