PD-L1-directed PlGF/VEGF blockade synergizes with chemotherapy by targeting CD141+ cancer-associated fibroblasts in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year overall survival rate. Patients with PDAC display limited benefits after undergoing chemotherapy or immunotherapy modalities. Herein, we reveal that chemotherapy upregulates placental growth factor (PlGF), which directly activates cancer-associated fibroblasts (CAFs) to induce fibrosis-associated collagen deposition in PDAC. Patients with poor prognosis have high PIGF/VEGF expression and an increased number of PIGF/VEGF receptor-expressing CAFs, associated with enhanced collagen deposition. We also develop a multi-paratopic VEGF decoy receptor (Ate-Grab) by fusing the single-chain Fv of atezolizumab (anti-PD-L1) to VEGF-Grab to target PD-L1-expressing CAFs. Ate-Grab exerts anti-tumor and anti-fibrotic effects in PDAC models via the PD-L1-directed PlGF/VEGF blockade. Furthermore, Ate-Grab synergizes with gemcitabine by relieving desmoplasia. Single-cell RNA sequencing identifies that a CD141+ CAF population is reduced upon Ate-Grab and gemcitabine combination treatment. Overall, our results elucidate the mechanism underlying chemotherapy-induced fibrosis in PDAC and highlight a combinatorial therapeutic strategy for desmoplastic cancers.

Tumour organoids and assembloids: Patient‐derived cancer avatars for immunotherapy

“…Copyright 2021 Elsevier B.V.), (D) ECM (Reproduced with permission from Ref. 206 . Copyright 2022 Springer Nature), (E) exosomes or extracellular vesicles (Reproduced with permission from Ref.…”

Ultrasound combined with microbubble mediated immunotherapy for tumor microenvironment

“…At present, the use of effective vascular therapy for anti-tumor has been extensively studied. In the past clinical studies, the application of VEGF pathway inhibitors showed more effective anti-tumor effects, such as several inhibitors targeting VEGF pathway ( Ranieri et al, 2006 ; Costache et al, 2015 ; Kim et al, 2022 ), including bevacizumab and gemcitabine. In the experiment of pancreatic cancer in mice, blocking BICC1/LCN2 signal pathway can reduce the microvessel density and tumor volume of mouse PAAD cell grafts, enhance the antitumor effect of gemcitabine, and delay tumor growth ( Kooiman et al, 2020 ).…”

Cancer-associated fibroblasts: from basic science to anticancer therapy

“…Chemotherapy resistance in PDAC is often associated with desmoplasia 93 , 94 , one of which was recently shown to occur through PlGF/VEGF-mediated activation of CAFs in an orthotopic PDAC mouse model treated with gemcitabine 95 . Therefore, the authors delicately designed and synthesized a multiparatopic VEGF decoy receptor (Ate-Grab), a fusion protein consisting of single-chain Fv of atezolizumab for targeting PD-L1-rich tumor tissues, fused to VEGF-Grab, which was previously developed to target PIGF/VEGF 96 , resulting in PD-L1-directed PlGF/VEGF blockade.…”

“…Therefore, the authors delicately designed and synthesized a multiparatopic VEGF decoy receptor (Ate-Grab), a fusion protein consisting of single-chain Fv of atezolizumab for targeting PD-L1-rich tumor tissues, fused to VEGF-Grab, which was previously developed to target PIGF/VEGF 96 , resulting in PD-L1-directed PlGF/VEGF blockade. Indeed, Ate-Grab treatment relieved chemotherapy-induced desmoplasia in a PDAC model by sequestering PlGF/VEGF within the TME and thus inhibiting CAF activation, especially the CD141 + population, a key subset activated by gemcitabine treatment responsible for tumor fibrosis 95 .…”