Key result
Combined blockade of VEGFA and ANGPT2 with CD40 agonistic antibodies promoted antiangiogenic and immunostimulatory reprogramming, destroying tumor fibrosis and unleashing T cell-mediated killing in chemoresistant Prox1-deficient intestinal tumors.
Why the study?
Patients with desmoplastic colorectal cancer have a worse prognosis and do not benefit from chemotherapy, but the mechanisms underlying differential responses of APC-mutant CRCs to chemotherapy are not well understood.
In Prox1-deficient desmoplastic colorectal cancer models, combining VEGFA/ANGPT2 blockade with CD40 agonism overcomes chemoresistance and immunosuppression.
Answers are grounded in this paper and cite their sources.
May guide therapy in chemoresistant intestinal tumors; hypothesis-generating and leaves clinical translation open.
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.
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Ragusa et al. (2020) studied Colorectal cancer. Anti-VEGFA/ANGPT2 (A2V) and CD40 agonistic antibody vs. Control or monotherapy was evaluated on Tumor growth and T cell-mediated killing. Combined blockade of VEGFA and ANGPT2 with CD40 agonistic antibodies promoted antiangiogenic and immunostimulatory reprogramming, destroying tumor fibrosis and unleashing T cell-mediated killing in chemoresistant Prox1-deficient intestinal tumors.
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