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Engineering ROS-Responsive Bioscaffolds for Disrupting Myeloid Cell-Driven Immunosuppressive Niche to Enhance PD-L1 Blockade-Based Postablative Immunotherapy.

ABSTRACT: The existence of inadequate ablation remains an important cause of treatment failure for loco-regional ablation therapies. Here, using a preclinical model, it is reported that inadequate microwave ablation (iMWA) induces immunosuppressive niche predominated by myeloid cells. The gene signature of ablated tumor presented by transcriptome analyses is highly correlated with immune checkpoint blocking (ICB) resistance. Thus, an in situ scaffold with synergistic delivery of IPI549 and anti-programmed death-ligand 1 blocking antibody (aPDL1) for postablative cancer immunotherapy is designed and engineered, in which IPI549 capable of targeting myeloid cells could disrupt the immunosuppressive niche and subsequently improve ICB-mediated antitumor immune response. Based on five mouse cancer models, it is demonstrated that this biomaterial system (aPDL1&IPI549@Gel) could mimic a "hot" tumor-immunity niche to inhibit tumor progression and metastasis, and protect cured mice against tumor rechallenge. This work enables a new standard-of-care paradigm for the immunotherapy of myeloid cells-mediated "cold" tumors after loco-regional inadequate practices.

SUBMITTER: Li S

PROVIDER: S-EPMC9008797 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Engineering ROS-Responsive Bioscaffolds for Disrupting Myeloid Cell-Driven Immunosuppressive Niche to Enhance PD-L1 Blockade-Based Postablative Immunotherapy.

Li Shaoyue S Zhu Chunyan C Zhou Xianli X Chen Liang L Bo Xiaowan X Shen Yuting Y Guan Xin X Han Xiaoxia X Shan Dandan D Sun Liping L Chen Yu Y Xu Huixiong H Yue Wenwen W

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20220213 11

The existence of inadequate ablation remains an important cause of treatment failure for loco-regional ablation therapies. Here, using a preclinical model, it is reported that inadequate microwave ablation (iMWA) induces immunosuppressive niche predominated by myeloid cells. The gene signature of ablated tumor presented by transcriptome analyses is highly correlated with immune checkpoint blocking (ICB) resistance. Thus, an in situ scaffold with synergistic delivery of IPI549 and anti-programmed ...[more]

PMID: 35156339

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Project description:BackgroundImmunotherapy is beneficial for some colorectal cancer (CRC) patients, but immunosuppressive networks limit its effectiveness. Cancer-associatedfibroblasts (CAFs) are significant in immune escape and resistance toimmunotherapy, emphasizing the urgent need for new treatment strategies.MethodsFlow cytometric, Western blotting, proteomics analysis, analysis of public database data, genetically modified cell line models, T cell coculture, crystal violetstaining, ELISA, metabonomic and clinical tumour samples were conducted to assess the role of EDEM3 in immune escape and itsmolecular mechanisms. We evaluated theeffects of FMD plus 2-DG on antitumour immunity using multipleximmunofluorescence, flow cytometry, cytokine profiling, TUNEL assays, xenografttumours, and in vivo studies.ResultsWe show thatCAFs upregulate PD-L1 glycosylation and contribute to immune evasion byglycosyltransferase EDEM3. Additionally, EDEM3 plays a role in tumour immunityduring tumour progression. However, the EDEM3-mediated upregulation of PD-L1 expression underpins PD-1/PD-L1 blockade resistance in vivo. This finding contradictsthe previous trend that positive PD-L1 expression indicates a strong responseto PD-1/PD-L1 blockade. Mechanistically, high-EDEM3 expression facilitates M2-like This finding contradictsthe previous trend that positive PD-L1 expression indicates a strong responseto PD-1/PD-L1 blockade.Mechanistically, polarizationand chemotactic migration of macrophages, which are enriched in theperipheral region of tumours compared to thecore region, precluding access of CD8+ T cells to tumourfoci. Furthermore, we EDEM3 predominantly activates the recruited M2-like macrophagesvia a glucose metabolism-dependent mechanism. Manipulationof glucose utilization by a fasting-mimicking diet(FMD) plus 2-DG treatmentsynergistically with PD-1 antibody elicits potent antitumour activity byeffectively decreasing tumour glycosylated PD-L1 expression, augmenting the CD8+effector T cell infiltration and activation while concurrently reducing the infiltration.TheCAFs-EDEM3-M2-like macrophage axis plays a critical role in promotingimmunotherapy resistance. infiltration.TheCAFs-EDEM3-M2-like macrophage axis plays a critical role in promotingimmunotherapy resistance.ConclusionsOur study suggests that blocking EDEM3-induced M2-like macro phage trafficking by FMD plus 2-DG is a promising and effective strategy to overcomeresistance to checkpoint blockade therapy offeringhope for improved treatment outcomes.Key pointsCancer-associated fibroblasts (CAFs) can enhance PD-L1 glycosylation through the glycosyltransferase EDEM3, contributing to immune evasion during tumour progression. EDEM3 predominantly activates the recruit M2-like macrophages via a glucose metabolism-dependent mechanism. Blocking glucose utilization antagonizes recruiting and polarizing M2-like macrophages synergistically with PD-1 antibody to improve anticancer immunity.

Dataset Information

Engineering ROS-Responsive Bioscaffolds for Disrupting Myeloid Cell-Driven Immunosuppressive Niche to Enhance PD-L1 Blockade-Based Postablative Immunotherapy.

Publications

Engineering ROS-Responsive Bioscaffolds for Disrupting Myeloid Cell-Driven Immunosuppressive Niche to Enhance PD-L1 Blockade-Based Postablative Immunotherapy.

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