The Interplay between Integrins and Immune Cells as a Regulator in Cancer Immunology

Zhang, Qingfang; Zhang, Shuo; Chen, Jianrui; Xie, Zhenzhen

doi:10.3390/ijms24076170

Cited by 16 publications

(7 citation statements)

References 251 publications

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“…Integrins have long been recognized to be essential for cell adhesion, migration, and invasion. ITG-α3, in particular, has been implicated in promoting metastasis in various types of cancers, including BC [30,63]. Given the observed interaction between Cav-1 and ITG-α3 in our study, it is possible that a combination of Cav-1-and ITG-α3-targeted therapies could exert a synergistic effect on inhibiting metastasis.…”

Section: Discussionmentioning

confidence: 63%

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Caveolin-1 Knockout Mitigates Breast Cancer Metastasis to the Lungs via Integrin α3 Dysregulation.

Francis,

Singh,

Pathak

et al. 2023

Preprint

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Caveolin-1 (Cav-1) is a critical lipid raft protein playing divergent roles as both a tumor suppressor and promoter. While its role in tumorigenesis, progression, and metastasis is recognized, explicit contribution of Cav-1 to the onset of lung metastasis from primary breast malignancies remained vague. We exhibit here, the first-ever evidence of Cav-1 knockout in epithelial cells leading to a significant reduction in lung metastasis in syngeneic mouse models of breast cancer. In vitro, Cav-1 knockout in 4T1 cells suppressed extracellular vesicles secretion, cellular motility, and MMP secretion vis-à-vis the controls. Complementing this, our in vivo analyses demonstrated a marked reduction in lung metastatic foci in mice injected with Cav-1 knockout 4T1 cells as compared to wild-type mice, which was further corroborated by mRNA profiling of the primary tumor. We discerned 21 epithelial cell migration genes exhibiting varied expression in tumors derived from Cav-1 knockout versus wild-type 4T1 cells. Correlation analysis and immunoblotting further divulged that Cav-1 regulates metastasis via integrin α3 (ITGα3). In silico protein docking anticipated an interaction between Cav-1 and ITGα3, substantiated by co-immunoprecipitation. Furthermore, ITGα3 knockdown corroborated its role in metastasis in a cell migration assay. Therefore, it can be inferred that Cav-1 plays a pivotal role in the pre-metastatic niche establishment and facilitates lung-specific cell migration.

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Section: Discussionmentioning

confidence: 63%

“…Additionally, Cav-1 promotes the deposition of extracellular matrix by lung broblasts and facilitates angiogenesis by inducing M2 macrophage polarization [25]. In hepatocellular carcinoma, Cav-1 was shown to enhance invasion and metastasis by upregulating Pofut1 expression [30], suggesting a broader oncogenic role.…”

Section: Introductionmentioning

confidence: 99%

Caveolin-1 Knockout Mitigates Breast Cancer Metastasis to the Lungs via Integrin α3 Dysregulation.

Francis,

Singh,

Pathak

et al. 2023

Preprint

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“…The integrins that function primarily as collagen receptors are α1β1, α2β1, α3β1, α10β1 and α11β1 ( 67 ). The interplay between integrins and immune cells for cancer immunity and the role of integrin receptor interactions with the TME-ECM and targeting for cancer therapy is beyond the scope of this review and has been reviewed elsewhere ( 68 , 69 ).…”

Section: Tumor Ecm Ligands Interact With Immune Cell Receptorsmentioning

confidence: 99%

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

Flies,

Langermann,

Jensen

et al. 2023

Front. Immunol.

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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.

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“…On the other hand, the most significant functional term for ligandreceptor interactions unique to patients with long survival was integrin signaling, which included numerous interactions among integrins and collagens (Supplemental Figure 5). Integrin engagement plays a major role in effective immune activation by promoting immune cell aggregation and TCR signaling 41,42 .…”

Section: The Immune-suppressive Cellular Microenvironment Of Lymphoma...mentioning

confidence: 99%

Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease

Khaled,

Ren,

Kundalia

et al. 2023

Preprint

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Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor survival outcomes. We utilized comprehensive multi-omics analyses of CSF from patients with lymphoma LMD to demonstrate an immunosuppressive cellular microenvironment and identified dysregulations in proteins and lipids indicating neurodegenerative processes. Strikingly, we found a significant accumulation of toxic branched-chain keto acids (BCKA) in the CSF of patients with LMD. The BCKA accumulation was found to be a pan-cancer occurrence, evident in lymphoma, breast cancer, and melanoma LMD patients. Functionally, BCKA disrupted the viability and function of endogenous T lymphocytes, chimeric antigen receptor (CAR) T cells, neurons, and meningeal cells. Treatment of LMD mice with BCKA-reducing sodium phenylbutyrate significantly improved neurological function, survival outcomes, and efficacy of anti-CD19 CAR T cell therapy. This is the first report of BCKA accumulation in LMD and provides preclinical evidence that targeting these toxic metabolites improves outcomes.

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The Interplay between Integrins and Immune Cells as a Regulator in Cancer Immunology

Cited by 16 publications

References 251 publications

Caveolin-1 Knockout Mitigates Breast Cancer Metastasis to the Lungs via Integrin α3 Dysregulation.

Caveolin-1 Knockout Mitigates Breast Cancer Metastasis to the Lungs via Integrin α3 Dysregulation.

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

Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease

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