1. Combined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors
- Author
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Alessandra Castiglioni, Yagai Yang, Katherine Williams, Alvin Gogineni, Ryan S. Lane, Amber W. Wang, Justin A. Shyer, Zhe Zhang, Stephanie Mittman, Alan Gutierrez, Jillian L. Astarita, Minh Thai, Jeffrey Hung, Yeqing Angela Yang, Tony Pourmohamad, Patricia Himmels, Marco De Simone, Justin Elstrott, Aude-Hélène Capietto, Rafael Cubas, Zora Modrusan, Wendy Sandoval, James Ziai, Stephen E. Gould, Wenxian Fu, Yulei Wang, James T. Koerber, Shomyseh Sanjabi, Ira Mellman, Shannon J. Turley, and Sören Müller
- Subjects
Science - Abstract
Abstract 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 (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 IFNγhi 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 TSCL expansion and replacement of exhausted CD8 T cells, thereby maintaining the T cell compartment in a dysfunctional state.
- Published
- 2023
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