Combined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors
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Published:2023-08-05
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Castiglioni AlessandraORCID, Yang Yagai, Williams KatherineORCID, Gogineni Alvin, Lane Ryan S.ORCID, Wang Amber W., Shyer Justin A., Zhang ZheORCID, Mittman Stephanie, Gutierrez Alan, Astarita Jillian L., Thai Minh, Hung Jeffrey, Yang Yeqing Angela, Pourmohamad Tony, Himmels Patricia, De Simone Marco, Elstrott Justin, Capietto Aude-Hélène, Cubas Rafael, Modrusan Zora, Sandoval Wendy, Ziai James, Gould Stephen E., Fu Wenxian, Wang YuleiORCID, Koerber James T.ORCID, Sanjabi ShomysehORCID, Mellman IraORCID, Turley Shannon J.ORCID, Müller SörenORCID
Abstract
AbstractTGFβ signaling is associated with non-response to immune checkpoint blockade in patients with advanced cancers, particularly in the immune-excluded phenotype. While previous work demonstrates that converting tumors from excluded to inflamed phenotypes requires attenuation of PD-L1 and TGFβ signaling, the underlying cellular mechanisms remain unclear. Here, we show that TGFβ and PD-L1 restrain intratumoral stem cell-like CD8 T cell (TSCL) expansion and replacement of progenitor-exhausted and dysfunctional CD8 T cells with non-exhausted T effector cells in the EMT6 tumor model in female mice. Upon combined TGFβ/PD-L1 blockade IFNγhiCD8 T effector cells show enhanced motility and accumulate in the tumor. Ensuing IFNγ signaling transforms myeloid, stromal, and tumor niches to yield an immune-supportive ecosystem. Blocking IFNγ abolishes the anti-PD-L1/anti-TGFβ therapy efficacy. Our data suggest that TGFβ works with PD-L1 to prevent TSCLexpansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference113 articles.
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