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Article: IL-6 trans-signaling promotes the expansion and anti-tumor activity of CAR T cells

TitleIL-6 trans-signaling promotes the expansion and anti-tumor activity of CAR T cells
Authors
Issue Date2021
PublisherSpringer Nature [academic journals on nature.com]. The Journal's web site is located at http://www.nature.com/leu
Citation
Leukemia, 2021, v. 35 n. 5, p. 1380-1391 How to Cite?
AbstractChimeric antigen receptor (CAR) T cell therapies lead to high clinical response rates in B cell malignancies, and are under investigation for treatment of solid tumors. While high systemic interleukin- (IL-) 6 levels are associated with clinical cytokine release syndrome (CRS), the role of IL-6 trans-signaling within CAR T-cells has not been reported. We generated CAR T cells that constitutively express hyper IL-6 (HIL-6), a designer cytokine that activates the trans-signaling pathway. HIL-6-expressing CAR T-cells exhibited enhanced proliferation and antitumor efficacy in vitro and in xenograft models. However, HIL-6 CAR T cells caused severe graft-versus-host disease (GVHD). Transcriptomic profiling revealed that HIL-6 stimulation of CAR T cells upregulated genes associated with T cell migration, early memory differentiation, and IL-6/GP130/STAT3 signaling. Since IL-6 trans-signaling acts via surface GP130, we generated CAR T cells expressing a constitutively-active form of GP130 and found these retained improved antitumor activity without signs of GVHD in preclinical models of B-cell leukemia and solid tumors. Taken together, these results show that IL-6 trans-signaling can enhance expansion and antitumor activity of CAR T cells via the GP130/STAT3 pathway, and suggest that expression of GP130 within CAR T cells could lead to improved antitumor efficacy without systemic IL-6 trans-signaling.
Persistent Identifierhttp://hdl.handle.net/10722/295771
ISSN
2020 Impact Factor: 11.528
2020 SCImago Journal Rankings: 4.539
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorJiang, Z-
dc.contributor.authorLiao, R-
dc.contributor.authorLv, J-
dc.contributor.authorLi, S-
dc.contributor.authorZheng, D-
dc.contributor.authorQin, L-
dc.contributor.authorWu, D-
dc.contributor.authorChen, S-
dc.contributor.authorLong, Y-
dc.contributor.authorWu, Q-
dc.contributor.authorWang, S-
dc.contributor.authorLin, S-
dc.contributor.authorHuang, X-
dc.contributor.authorTang, Z-
dc.contributor.authorShi, P-
dc.contributor.authorZhou, H-
dc.contributor.authorLiu, Q-
dc.contributor.authorZhao, R-
dc.contributor.authorLi, Y-
dc.contributor.authorJie, Y-
dc.contributor.authorWei, W-
dc.contributor.authorLai, P-
dc.contributor.authorDu, X-
dc.contributor.authorCiu, S-
dc.contributor.authorWeinkove, R-
dc.contributor.authorLiu, P-
dc.contributor.authorPei, D-
dc.contributor.authorYao, Y-
dc.contributor.authorLi, P-
dc.date.accessioned2021-02-08T08:13:46Z-
dc.date.available2021-02-08T08:13:46Z-
dc.date.issued2021-
dc.identifier.citationLeukemia, 2021, v. 35 n. 5, p. 1380-1391-
dc.identifier.issn0887-6924-
dc.identifier.urihttp://hdl.handle.net/10722/295771-
dc.description.abstractChimeric antigen receptor (CAR) T cell therapies lead to high clinical response rates in B cell malignancies, and are under investigation for treatment of solid tumors. While high systemic interleukin- (IL-) 6 levels are associated with clinical cytokine release syndrome (CRS), the role of IL-6 trans-signaling within CAR T-cells has not been reported. We generated CAR T cells that constitutively express hyper IL-6 (HIL-6), a designer cytokine that activates the trans-signaling pathway. HIL-6-expressing CAR T-cells exhibited enhanced proliferation and antitumor efficacy in vitro and in xenograft models. However, HIL-6 CAR T cells caused severe graft-versus-host disease (GVHD). Transcriptomic profiling revealed that HIL-6 stimulation of CAR T cells upregulated genes associated with T cell migration, early memory differentiation, and IL-6/GP130/STAT3 signaling. Since IL-6 trans-signaling acts via surface GP130, we generated CAR T cells expressing a constitutively-active form of GP130 and found these retained improved antitumor activity without signs of GVHD in preclinical models of B-cell leukemia and solid tumors. Taken together, these results show that IL-6 trans-signaling can enhance expansion and antitumor activity of CAR T cells via the GP130/STAT3 pathway, and suggest that expression of GP130 within CAR T cells could lead to improved antitumor efficacy without systemic IL-6 trans-signaling.-
dc.languageeng-
dc.publisherSpringer Nature [academic journals on nature.com]. The Journal's web site is located at http://www.nature.com/leu-
dc.relation.ispartofLeukemia-
dc.titleIL-6 trans-signaling promotes the expansion and anti-tumor activity of CAR T cells-
dc.typeArticle-
dc.identifier.emailLiu, P: pliu88@hku.hk-
dc.identifier.authorityLiu, P=rp02328-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/s41375-020-01085-1-
dc.identifier.pmid33168950-
dc.identifier.scopuseid_2-s2.0-85095694858-
dc.identifier.hkuros321223-
dc.identifier.volume35-
dc.identifier.issue5-
dc.identifier.spage1380-
dc.identifier.epage1391-
dc.identifier.isiWOS:000587938600001-
dc.publisher.placeUnited Kingdom-

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