Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

Nicolas‐Boluda, Alba; Vaquero, Javier; Barrin, Sarah; Kantari‐Mimoun, Chahrazade; Ponzo, Matteo; Renault, Gilles; Deptuła, Piotr; Pogoda, Katarzyna; Bucki, Robert; Cascone, Ilaria; Courty, José; Fouassier, Laura; Gazeau, Florence; Donnadieu, Emmanuel

doi:10.1101/2020.05.19.104430

Cited by 24 publications

(38 citation statements)

References 57 publications

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“…Based on the impacts of ECM on T‐cell, a novel lysyl oxidase (LOX) target strategy was used to modulate the mechanotransduction and clinical efficiency of T‐cell by altering the mechanical properties of the microenvironments which can be extensively adopted in various in vivo and ex vivo platforms. [ 112 ] By developing these 3D scaffolds and organoid systems and protocols, we can gain valuable insights on the CAR T‐cell mechanoimmunology that are truly physiologically relevant.…”

Section: Current Bioengineering Strategies For Deciphering T‐cell Mecmentioning

confidence: 99%

The CAR T‐Cell Mechanoimmunology at a Glance

Cai

et al. 2020

Advanced Science

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Chimeric antigen receptor (CAR) T-cell transfer is a novel paradigm of adoptive T-cell immunotherapy. When coming into contact with a target cancer cell, CAR T-cell forms a nonclassical immunological synapse with the cancer cell and dynamically orchestrates multiple critical forces to commit cytotoxic immune function. Such an immunologic process involves a force transmission in the CAR and a spatiotemporal remodeling of cell cytoskeleton to facilitate CAR activation and CAR T-cell cytotoxic function. Yet, the detailed understanding of such mechanotransduction at the interface between the CAR T-cell and the target cell, as well as its molecular structure and signaling, remains less defined and is just beginning to emerge. This article summarizes the basic mechanisms and principles of CAR T-cell mechanoimmunology, and various lessons that can be comparatively learned from interrogation of mechanotransduction at the immunological synapse in normal cytotoxic T-cell. The recent development and future application of novel bioengineering tools for studying CAR T-cell mechanoimmunology is also discussed. It is believed that this progress report will shed light on the CAR T-cell mechanoimmunology and encourage future researches in revealing the less explored yet important mechanosensing and mechanotransductive mechanisms involved in CAR T-cell immuno-oncology.

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Section: Current Bioengineering Strategies For Deciphering T‐cell Mecmentioning

confidence: 99%

The CAR T‐Cell Mechanoimmunology at a Glance

Cai

et al. 2020

Advanced Science

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“…Cell migration reactome terms were also included in the analysis. In the IDH1 wild-type background, degradation of keratan sulfate, which can interact with neuroregulatory ligands, dissolution of fibrin clot, and crosslinking of collagen fibrils, which are important for tumor cell and T cell migration, were higher than those in the IDH1 mutant [16][17][18]. Activation of NIMA kinases, which induce premature mitosis, is highly activated in tumors with IDH1 wild-type [19,20].…”

Section: Discussionmentioning

confidence: 99%

Age-dependent Non-silent Somatic Mutation with Transcriptomic Landscape and Prognosis of Lower Grade Glioma

Park¹,

J²,

Jy³

et al. 2021

Preprint

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Glioma accounts for 80% of all malignant brain tumors and is the most common adult primary brain tumor. Age is an important factor affecting the development of cancer as somatic mutations accumulate with age. In this study, we aimed to analyze the significance of age-related non-silent somatic mutations in glioma prognosis. Histological tumor grade depends on age at diagnosis in patients with IDH1, TP53, ATRX, and EGFR mutations. The hierarchical clustering of patients was dominantly separated by IDH1 and EGFR mutations. Furthermore, patients with IDH1 mutation were dominantly separated by TP53 and ATRX double mutation and its double wildtype counterpart. Patients with the double mutation showed poorer prognosis than those with the double wild type genotype. In conclusion, among the many somatic mutations, those in IDH1, TP53, ATRX, and EGFR are important for glioma classification based on histological grade. Patients with EGFR mutation had the poorest prognosis, whereas those with only IDH1 mutation showed the best prognosis.

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“…The density and direction of the ECM influence the behavior and migration of T cells in human lung cancer. T cells generally accumulate in areas with loose stromal fibers ( 103 ), and a dense ECM serves as a contact barrier between T cells and the tumor cells ( 104 ). It also prevents T cells from binding PD-1 inhibitors, and thus promotes the resistance of tumor cells to immune checkpoint inhibitors ( 103 ).…”

Section: Roles and Mechanisms Of Cafs In Nsclc Drug Resistancementioning

confidence: 99%

“…The ECM includes collagen, laminin and fibronectin. Lysyl oxidase crosslinks collagen molecules into fibers to form a dense ECM, which inhibits the migration of T cells and reduces the effect of PD-1 inhibitors ( 104 ). In a xenograft model of NSCLC, CAFs overexpressing lysyl oxidase like-1 were found to remodel the collagen matrix in vivo ( 105 ), suggesting that CAFs promote NSCLC resistance to immunotherapeutic drugs through the ECM.…”

Section: Roles and Mechanisms Of Cafs In Nsclc Drug Resistancementioning

confidence: 99%

“…CAFs are the primary producers of TGF-β ( 106 ) and can influence T cell infiltration via TGF-β. TGF-β signaling was demonstrated to inhibit T cell infiltration in breast mouse tumor models ( 104 ). CAFs specifically inhibit CD8+ T cell infiltration, thereby promoting tumor resistance to different immunosuppressive agents ( 107 ).…”

Section: Roles and Mechanisms Of Cafs In Nsclc Drug Resistancementioning

confidence: 99%

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Role of cancer‑associated fibroblasts in the resistance to antitumor therapy, and their potential therapeutic mechanisms in non‑small cell lung cancer (Review)

Chen

Hou

et al. 2021

Oncol Lett

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Non-small cell lung cancer (NSCLC) is a malignant tumor with high morbidity and mortality rates, which seriously endangers human health. Although treatment methods continue to evolve, the emergence of drug resistance is inevitable and seriously hinders the treatment of NSCLC. The tumor microenvironment (TME) protects tumor cells from the effects of chemotherapeutic drugs, which can lead to drug resistance. Cancer-associated fibroblasts (CAFs) are an important component of the TME, and various studies have demonstrated that CAFs play a crucial role in drug resistance in NSCLC. However, the drug resistance mechanism of CAFs and whether CAFs can be used as a target to reverse the resistance of tumor cells remain unclear. The present review discusses this issue and describes the heterogeneity of CAF markers, as well as their origins and resident organs, and the role and mechanism of this heterogeneity in NSCLC progression. Furthermore, the mechanism of CAF-mediated NSCLC resistance to chemotherapy, targeted therapy and immunotherapy is introduced, and strategies to reverse this resistance are described.

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Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

Cited by 24 publications

References 57 publications

The CAR T‐Cell Mechanoimmunology at a Glance

The CAR T‐Cell Mechanoimmunology at a Glance

Age-dependent Non-silent Somatic Mutation with Transcriptomic Landscape and Prognosis of Lower Grade Glioma

Role of cancer‑associated fibroblasts in the resistance to antitumor therapy, and their potential therapeutic mechanisms in non‑small cell lung cancer (Review)

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