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Castiglioni, Alessandra; Yang, Yagai; Williams, Katherine; Gogineni, Alvin; Lane, Ryan S; Wang, Amber W; Shyer, Justin A; Zhang, Zhe; 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, Yulei; Koerber, James T; Sanjabi, Shomyseh; Mellman, Ira; Turley, Shannon J; Müller, Sören
Nature communications, 08/2023, Letnik: 14, Številka: 1Journal Article
TGFβ 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 (T ) 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 IFNγ CD8 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 T expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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