Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors

Zebin Xiao, Leslie Todd, Li Huang, Estela Noguera-Ortega, Zhen Lu, Lili Huang, Meghan Kopp, Yue Li, Nimisha Pattada, Wenqun Zhong, Wei Guo, John Scholler, Maria Liousia, Charles-Antoine Assenmacher, Carl H. June, Steven M. Albelda and Ellen Puré ()
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Zebin Xiao: University of Pennsylvania
Leslie Todd: University of Pennsylvania
Li Huang: University of Pennsylvania
Estela Noguera-Ortega: University of Pennsylvania
Zhen Lu: University of Pennsylvania
Lili Huang: University of Pennsylvania
Meghan Kopp: University of Pennsylvania
Yue Li: University of Pennsylvania
Nimisha Pattada: University of Pennsylvania
Wenqun Zhong: University of Pennsylvania
Wei Guo: University of Pennsylvania
John Scholler: University of Pennsylvania
Maria Liousia: University of Pennsylvania
Charles-Antoine Assenmacher: University of Pennsylvania
Carl H. June: University of Pennsylvania
Steven M. Albelda: University of Pennsylvania
Ellen Puré: University of Pennsylvania

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract The desmoplastic stroma in solid tumors presents a formidable challenge to immunotherapies that rely on endogenous or adoptively transferred T cells, however, the mechanisms are poorly understood. To define mechanisms involved, here we treat established desmoplastic pancreatic tumors with CAR T cells directed to fibroblast activation protein (FAP), an enzyme highly overexpressed on a subset of cancer-associated fibroblasts (CAFs). Depletion of FAP+ CAFs results in loss of the structural integrity of desmoplastic matrix. This renders these highly treatment-resistant cancers susceptible to subsequent treatment with a tumor antigen (mesothelin)-targeted CAR T cells and to anti-PD-1 antibody therapy. Mechanisms include overcoming stroma-dependent restriction of T cell extravasation and/or perivascular invasion, reversing immune exclusion, relieving T cell suppression, and altering the immune landscape by reducing myeloid cell accumulation and increasing endogenous CD8+ T cell and NK cell infiltration. These data provide strong rationale for combining tumor stroma- and malignant cell-targeted therapies to be tested in clinical trials.

Date: 2023
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DOI: 10.1038/s41467-023-40850-5

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