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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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, and Sanjabi, Shomyseh
- Subjects
Female ,Animals ,Mice ,Cell Differentiation ,CD8-Positive T-Lymphocytes ,Stem Cells ,B7-H1 Antigen ,Transforming Growth Factor beta ,Interferon-gamma ,T-Cell Exhaustion ,Immune Checkpoint Inhibitors ,Mice ,Inbred BALB C ,Cell Line ,Tumor ,Breast Neoplasms ,RNA-Seq - 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