Author:
Xiao Zebin,Todd Leslie,Huang Li,Noguera-Ortega Estela,Lu Zhen,Huang Lili,Kopp Meghan,Li Yue,Pattada Nimisha,Zhong Wenqun,Guo Wei,Scholler John,Liousia Maria,Assenmacher Charles-Antoine,June Carl H.,Albelda Steven M.,Puré Ellen
Abstract
AbstractThe 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, 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 and to anti-PD1 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.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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