Alan Nicolas Thierry Guichard

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Related research domains (1)
Vascular endothelial growth factor
Vascular endothelial growth factor (VEGF, vɛdʒ'ɛf), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. T
Related publications (4)

Overcoming microenvironmental resistance to PD-1 blockade in genetically engineered lung cancer models

Gael Luis Boivin, Chiara Cianciaruso, Michele De Palma, Alan Nicolas Thierry Guichard, Ece Kadioglu, Ioanna Keklikoglou, Amaia Martinez Usatorre, Etienne Meylan, Sina Nassiri, Bruno Torchia, Nadine Zangger

Immune checkpoint blockade (ICB) with PD-1 or PD-L1 antibodies has been approved for the treatment of nonsmall cell lung cancer (NSCLC). However, only a minority of patients respond, and sustained remissions are rare. Both chemotherapy and antiangiogenic drugs may improve the efficacy of ICB in mouse tumor models and patients with cancer. Here, we used genetically engineered mouse models of Kras(G12D/+);p53(-/-) NSCLC, including a mismatch repair-deficient variant (Kras(G12D/+);p53(-/-);Msh2(-/-)) with higher mutational burden, and longitudinal imaging to study tumor response and resistance to combinations of ICB, antiangiogenic therapy, and chemotherapy. Antiangiogenic blockade of vascular endothelial growth factor A and angiopoietin-2 markedly slowed progression of autochthonous lung tumors, but contrary to findings in other cancer types, addition of a PD-1 or PD-L1 antibody was not beneficial and even accelerated progression of a fraction of the tumors. We found that antiangiogenic treatment facilitated tumor infiltration by PD-1(+) regulatory T cells (T-regs), which were more efficiently targeted by the PD-1 antibody than CD8(+) T cells. Both tumor-associated macrophages (TAMs) of monocyte origin, which are colony-stimulating factor 1 receptor (CSF1R) dependent, and TAMs of alveolar origin, which are sensitive to cisplatin, contributed to establish a transforming growth factor-beta-rich tumor microenvironment that supported PD-1(+) T-regs. Dual TAM targeting with a combination of a CSF1R inhibitor and cisplatin abated T-regs, redirected the PD-1 antibody to CD8(+) T cells, and improved the efficacy of antiangiogenic immunotherapy, achieving regression of most tumors.

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice

Michele De Palma, Mauro Delorenzi, Nikolche Gjorevski, Alan Nicolas Thierry Guichard, Matthias Lütolf, Sina Nassiri, Simone Ragusa, Mario Leonardo Squadrito, Laureline Wetterwald

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.

Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy

Michele De Palma, Alan Nicolas Thierry Guichard, Daniela Pais Ferreira, Nicolo Rigamonti

Cancer immunotherapies are increasingly combined with targeted therapies to improve therapeutic outcomes. We show that combination of agonistic anti-CD40 with antiangiogenic antibodies targeting 2 proangiogenic factors, vascular endothelial growth factor A (VEGFA) and angiopoietin 2 (Ang2/ANGPT2), induces pleiotropic immune mechanisms that facilitate tumor rejection in several tumor models. On the one hand, VEGFA/Ang2 blockade induced regression of the tumor microvasculature while decreasing the proportion of nonperfused vessels and reducing leakiness of the remaining vessels. On the other hand, both anti-VEGFA/Ang2 and anti-CD40 independently promoted proinflammatory macrophage skewing and increased dendritic cell activation in the tumor microenvironment, which were further amplified upon combination of the 2 treatments. Finally, combined therapy provoked brisk infiltration and intratumoral redistribution of cytotoxic CD8+ T cells in the tumors, which was mainly driven by Ang2 blockade. Overall, these nonredundant synergistic mechanisms endowed T cells with improved effector functions that were conducive to more efficient tumor control, underscoring the therapeutic potential of antiangiogenic immunotherapy in cancer.
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