Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice.
J Clin Invest
; 130(3): 1199-1216, 2020 03 02.
Article
in En
| MEDLINE
| ID: mdl-32015230
ABSTRACT
Mutations in APC promote colorectal cancer (CRC) progression through uncontrolled WNT signaling. Patients with desmoplastic CRC have a significantly worse prognosis and do not benefit from chemotherapy, but the mechanisms underlying the differential responses of APC-mutant CRCs to chemotherapy are not well understood. We report that expression of the transcription factor prospero homeobox 1 (PROX1) was reduced in desmoplastic APC-mutant human CRCs. In genetic Apc-mutant mouse models, loss of Prox1 promoted the growth of desmoplastic, angiogenic, and immunologically silent tumors through derepression of Mmp14. Although chemotherapy inhibited Prox1-proficient tumors, it promoted further stromal activation, angiogenesis, and invasion in Prox1-deficient tumors. Blockade of vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2) combined with CD40 agonistic antibodies promoted antiangiogenic and immunostimulatory reprogramming of Prox1-deficient tumors, destroyed tumor fibrosis, and unleashed T cell-mediated killing of cancer cells. These results pinpoint the mechanistic basis of chemotherapy-induced hyperprogression and illustrate a therapeutic strategy for chemoresistant and desmoplastic CRCs.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colorectal Neoplasms
/
Drug Resistance, Neoplasm
/
Angiogenesis Inhibitors
/
Antineoplastic Agents, Immunological
/
Immunotherapy
/
Neovascularization, Pathologic
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Clin Invest
Year:
2020
Document type:
Article
Affiliation country:
Suiza