Regulation of tumor immunity and immunotherapy by the tumor collagen extracellular matrix

Abstract

It has been known for decades that the tumor extracellular matrix (ECM) is dysfunctional leading to loss of tissue architecture and promotion of tumor growth. The altered ECM and tumor fibrogenesis leads to tissue stiffness that act as a physical barrier to immune cell infiltration into the tumor microenvironment (TME). It is becoming increasingly clear that the ECM plays important roles in tumor immune responses. A growing body of data now indicates that ECM components also play a more active role in immune regulation when dysregulated ECM components act as ligands to interact with receptors on immune cells to inhibit immune cell subpopulations in the TME. In addition, immunotherapies such as checkpoint inhibitors that are approved to treat cancer are often hindered by ECM changes. In this review we highlight the ways by which ECM alterations affect and regulate immunity in cancer. More specifically, how collagens and major ECM components, suppress immunity in the complex TME. Finally, we will review how our increased understanding of immune and immunotherapy regulation by the ECM is leading towards novel disruptive strategies to overcome immune suppression.

Pan-cancer dissection of vasculogenic mimicry characteristic to provide potential therapeutic targets

“…Furthermore, we also found that VM cells, who are mainly influencer and mediator, have extensive and unique interactions with immune cells in the microenvironment through the LAMININ pathway ( Supplementary Figures S5B–D ). There have been previous reports that laminin is involved in immunosuppression, which indicates that the LAMININ pathway may also be an important way for VM to promote or mediate the formation of a suppressed immune microenvironment ( Simon et al, 2019 ; Phillippi et al, 2020 ; Lepucki et al, 2022 ; Flies et al, 2023 ). Moreover, we further analyzed the correlation between VM and immune response steps in KIRC.…”

“…Our research also indicated that VM cells are a type of cell in TME with the highest expression of TGFβ and interact extensively with immune cells through the TGFβ signaling pathway. In addition, VM cells interact uniquely with immune cells through laminin, which has been reported to have both immune promotion and suppression properties ( Huard et al, 1985 ; Simon et al, 2019 ; Phillippi et al, 2020 ; Lepucki et al, 2022 ; Flies et al, 2023 ). We speculate that VM cells may mediate immune evasion by utilizing its immunosuppressive effect.…”

Limitations and potential of immunotherapy in ovarian cancer

“…The ECM components also inhibit immune infiltration as well as the effector function of immune cells at the tumor site by directly providing cell adhesion and immunomodulatory ligands. Some of these receptors such as DDR-1, DDR-2, and LIAR-1 have been identified and targeted in this regard, improving survival outcomes ( 87 ).…”

Navigating the Immune Maze: Pioneering Strategies for Unshackling Cancer Immunotherapy Resistance

“…Strategies that modify the TME aim to disrupt the supportive network of the tumor, including alterations in blood flow and stromal cell inhibition. Such interventions highlight the TME's critical role in cancer therapy [97][98][99][100][101][102].…”