Combined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors

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 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 ()
Additional contact information
Alessandra Castiglioni: Genentech
Yagai Yang: Genentech
Katherine Williams: Genentech
Alvin Gogineni: Genentech
Ryan S. Lane: Genentech
Amber W. Wang: Genentech
Justin A. Shyer: Genentech
Zhe Zhang: Genentech
Stephanie Mittman: Genentech
Alan Gutierrez: Genentech
Jillian L. Astarita: Genentech
Minh Thai: Genentech
Jeffrey Hung: Genentech
Yeqing Angela Yang: Genentech
Tony Pourmohamad: Genentech
Patricia Himmels: Genentech
Marco Simone: Genentech
Justin Elstrott: Genentech
Aude-Hélène Capietto: Genentech
Rafael Cubas: Genentech
Zora Modrusan: Genentech
Wendy Sandoval: Genentech
James Ziai: Genentech
Stephen E. Gould: Genentech
Wenxian Fu: Genentech
Yulei Wang: Genentech
James T. Koerber: Genentech
Shomyseh Sanjabi: Genentech
Ira Mellman: Genentech
Shannon J. Turley: Genentech
Sören Müller: Genentech

Nature Communications, 2023, vol. 14, issue 1, 1-19

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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-40398-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40398-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-40398-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().