We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Combined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors.
- Authors
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
- 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. It has been previously shown that combining immune checkpoint inhibitors with TGFβ blockade potentiates anti-tumor immune responses. Here the authors show that, in an immune excluded preclinical tumor model, combining therapeutic anti-PD-L1 with anti-TGFβ treatment promotes expansion and differentiation of stem-cell like CD8 + T cells.
- Subjects
T cells; PROGRAMMED cell death 1 receptors; CD8 antigen; IMMUNE checkpoint proteins; IMMUNE checkpoint inhibitors; CANCER patients
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-40398-4