The extracellular matrix and immunity: breaking the old barrier in cancer

Vyas, Maulik; Demehri, Shadmehr

doi:10.1016/j.it.2022.04.004

Cited by 9 publications

(4 citation statements)

References 10 publications

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“…One example is LAIR-1, an inhibitory receptor expressed by leukocytes containing collagen-binding domains. [61][62][63] Another recent study found that fibronectin localization in the center of spheroids composed of small cell renal cell carcinoma cells regulated NK cell infiltration, further supporting a role for ECM components in NK cell migration. 64 These findings, along with data presented here, warrant further investigation, particularly in solid tumors such as PDAC.…”

Section: Discussionmentioning

confidence: 86%

Natural killer cells associate with epithelial cells in the pancreatic ductal adenocarcinoma tumor microenvironment

Malchiodi,

Suter,

Deshpande

et al. 2024

Preprint

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BackgroundPancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. PDAC’s poor prognosis and resistance to immunotherapy are attributed in part to its dense, fibrotic tumor microenvironment (TME), which is known to inhibit immune cell infiltration. We recently demonstrated that PDAC patients with higher natural killer (NK) cell content and activation have better survival rates. However, NK cell interactions in the PDAC TME have yet to be deeply studied. We show here that NK cells are present and active in the human PDAC TME.MethodsWe used imaging mass cytometry (IMC) to assess NK cell content, function, and spatial localization in human PDAC samples. Then, we used CellChat, a tool to infer ligand-receptor interactions, on a human PDAC scRNAseq dataset to further define NK cell interactions in PDAC.ResultsSpatial analyses showed for the first time that active NK cells are present in the PDAC TME, and both associate and interact with malignant epithelial cell ducts. We also found that fibroblast-rich, desmoplastic regions limit NK cell infiltration in the PDAC TME. CellChat analysis identified that the CD44 receptor on NK cells interacts with PDAC extracellular matrix (ECM) components such as collagen, fibronectin and laminin expressed by fibroblasts and malignant epithelial cells. This led us to hypothesize that these interactions play roles in regulating NK cell motility in desmoplastic PDAC TMEs. Using 2D and 3Din vitroassays, we found that CD44 neutralization significantly increased NK cell invasion through matrix.ConclusionsTargeting ECM-immune cell interactions may increase NK cell invasion into the PDAC TME.Graphical Abstract

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Section: Discussionmentioning

confidence: 86%

Natural killer cells associate with epithelial cells in the pancreatic ductal adenocarcinoma tumor microenvironment

Malchiodi,

Suter,

Deshpande

et al. 2024

Preprint

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“…Cancer cell invasion and metastasis possibly depend on this interaction [41]. Recent studies highlight the ECM as an active regulator of immunity in cancer [37,42,43] in addition to its known role in regulating the behavior of the CAFs in surrounding stroma [44]. In particular, macrophages, an important component of the TME of cancer tumors, are actively involved in the remodeling of cancer ECM.…”

Section: Extracellular Matrixmentioning

confidence: 99%

The Untouched Reserve of Cancer Chemotherapy: Tumor Cell Communication as a Promising Supramolecular Target

Alekseenko,

Zhukova,

Kondratyeva

et al. 2024

Preprint

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52 years have passed since President Nixon launched the "War on Cancer". The goals outlined by the President were not achieved because cancer treatment applied such as chemotherapy, radiotherapy, and targeted therapy have not fully met expectations. We suggest a new chemotherapeutic strategy: disrupting the communication between cancer cells and their microenvironment by chemical means. Immunological synapses that form between cancer cells and immune or other stromal cells provide an attractive target for this approach. Synapses form ligand-receptor clusters within interface of the interacting cells. Despite their differences, synapses share common properties: intercellular protein clusters; the proximity of these proteins; and their cooperative interaction making a synapse an unified functional unit. Synapses provide the limited space for the focused intercellular exchange of signaling molecules and particles. Therefore, destruction of synapses is expected to cause collapse of various tumor types. Additionally, the clustered arrangement of synapse components offers opportunities to increase treatment safety by reducing the concentration of cell impermeable agents used, to enhance its specificity applying cross-linking reagents, thus restricting modifications of surface-exposed molecules. By attaching a cleavable cell permeable toxic agent to a crosslinker should further enhance a killing potential in treating cancer. The proposed approach promises to be simple, universal, and less expensive than existing cancer therapy methods.

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“…In addition to CAF-secreted elements that directly influence CD8 + T cell control of migration and function in TME, it has been discovered that dense ECM structures can impede CD8 + T cell intratumoral migration (Vyas and Demehri, 2022).…”

Section: Direct Interaction Between Cafs and T Lymphocytesmentioning

confidence: 99%

CAFs orchestrates tumor immune microenvironment—A new target in cancer therapy?

et al. 2023

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Cancer immunotherapy has opened a new landscape in cancer treatment, however, the poor specificity and resistance of most targeted therapeutics have limited their therapeutic efficacy. In recent years, the role of CAFs in immune regulation has been increasingly noted as more evidence has been uncovered regarding the link between cancer-associated fibroblasts (CAFs) and the evolutionary process of tumor progression. CAFs interact with immune cells to shape the tumor immune microenvironment (TIME) that favors malignant tumor progression, a crosstalk process that leads to the failure of cancer immunotherapies. In this review, we outline recent advances in the immunosuppressive function of CAFs, highlight the mechanisms of CAFs-immune cell interactions, and discuss current CAF-targeted therapeutic strategies for future study.

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The extracellular matrix and immunity: breaking the old barrier in cancer

Cited by 9 publications

References 10 publications

Natural killer cells associate with epithelial cells in the pancreatic ductal adenocarcinoma tumor microenvironment

Natural killer cells associate with epithelial cells in the pancreatic ductal adenocarcinoma tumor microenvironment

The Untouched Reserve of Cancer Chemotherapy: Tumor Cell Communication as a Promising Supramolecular Target

CAFs orchestrates tumor immune microenvironment—A new target in cancer therapy?

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