Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice
Simone Ragusa, … , Michele De Palma, Tatiana V. Petrova
Simone Ragusa, … , Michele De Palma, Tatiana V. Petrova
Published February 4, 2020
Citation Information: J Clin Invest. 2020;130(3):1199-1216. https://doi.org/10.1172/JCI129558.
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Research Article Angiogenesis Oncology

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice

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.

Authors

Simone Ragusa, Borja Prat-Luri, Alejandra González-Loyola, Sina Nassiri, Mario Leonardo Squadrito, Alan Guichard, Sabrina Cavin, Nikolce Gjorevski, David Barras, Giancarlo Marra, Matthias P. Lutolf, Jean Perentes, Emily Corse, Roberta Bianchi, Laureline Wetterwald, Jaeryung Kim, Guillermo Oliver, Mauro Delorenzi, Michele De Palma, Tatiana V. Petrova

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Figure 1

High PROX1 expression is associated with better clinical outcomes and low stromal content.

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High PROX1 expression is associated with better clinical outcomes and lo...
(A) Kaplan-Meier overall survival curves for patients with high or low PROX1 levels in MSS CRC tumors (GEO GSE39582; n = 444). Progression-free survival showed the same trend but did not reach significance (P = 0.3). (B) PROX1 expression correlation with WNT pathway activation in MSS CRCs (GSE39582; n = 444). Dashed line indicates the locally estimated scatterplot smoothing (LOESS) fit. (C) PROX1 expression in CRC CMS subgroups (GSE39582; n = 409). CMS1 MSI-like (n = 21); CMS2 high WNT signaling (n = 217); CMS3 KRAS-mutant and metabolic alterations (n = 63); CMS4 TGF-β–driven stromal and angiogenic activation (n = 108). P < 0.001, by 1-way ANOVA with Tukey’s multiple comparisons test. P < 0.001, for CMS2 verus CMS1; P = 0.001, for CMS2 versus CMS3; P = 0.003, for CMS2 versus CMS4. (D) PROX1 expression in intrinsic CRIS subtypes. CRIS-A: BRAF- or KRAS-mutated, secretory (n = 88); CRIS-B TGF-β signaling, EMT features (n = 59); CRIS-C KRAS WT, high ERBB/EGFR pathway activity, MYC copy number gains (n = 119); CRIS-D: high WNT, IGF2 amplification, and FGFR autocrine stimulation (n = 96); CRIS-E: high WNT, Paneth-like phenotype, and TP53-mutations (n = 82) in GSE39582 (n = 444). P < 0.001, by 1-way ANOVA with Tukey’s multiple comparisons test. (E) PROX1 expression negatively correlated with a tumor stromal signature in MSS CRCs (GSE39582; n = 444). The stromal gene signature is from ref. 80. Enrichment was computed using single-sample GSEA (81). Dashed line indicates the linear regression fit. (F) Scatterplot of the negative correlation between scores for PROX1 protein nuclear expression levels in tumor cells and for stromal content over the total tumor area, in MSS primary CRC samples (n = 114). (G) Representative images of CRC adenocarcinomas with high and low PROX1 scores. PROX1 staining (brown) and DNA counterstaining (blue) are shown. Scale bars: 200 μm.