- Castiglioni, Alessandra;
- Yang, Yagai;
- Williams, Katherine;
- Gogineni, Alvin;
- Lane, Ryan;
- Wang, Amber;
- Shyer, Justin;
- Zhang, Zhe;
- Mittman, Stephanie;
- Gutierrez, Alan;
- Astarita, Jillian;
- Thai, Minh;
- Hung, Jeffrey;
- Yang, Yeqing;
- Pourmohamad, Tony;
- Himmels, Patricia;
- De Simone, Marco;
- Elstrott, Justin;
- Capietto, Aude-Hélène;
- Cubas, Rafael;
- Modrusan, Zora;
- Sandoval, Wendy;
- Ziai, James;
- Gould, Stephen;
- Fu, Wenxian;
- Wang, Yulei;
- Koerber, James;
- Mellman, Ira;
- Turley, Shannon;
- Müller, Sören;
- Sanjabi, Shomyseh
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.