JAML promotes CD8 and γδ T cell antitumor immunity and is a novel target for cancer immunotherapy

McGraw, Joseph M.; Thelen, Flavian; Hampton, Eric; Bruno, Nelson E.; Young, Travis S.; Havran, Wendy L.; Witherden, Deborah A.

doi:10.1084/jem.20202644

Cited by 17 publications

(22 citation statements)

References 53 publications

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“…However, changes in expression and function of CAR during carcinogenesis may be tumor-specific and both positive and negative expression contribute to different aspects of tumor progression ( 19 ). Our data demonstrate that CAR expression levels are highest at the boundary between the tumor edge and the stroma, in agreement with another recent study ( 28 ). Moreover, we show that CAR is a mechanosensitive protein and undergoes enhanced phosphorylation in response to stiffness.…”

Section: Discussionsupporting

confidence: 94%

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CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion

et al. 2022

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The coxsackie and adenovirus receptor (CAR) is a member of the junctional adhesion molecule (JAM) family of adhesion receptors and is localised to epithelial cell tight and adherens junctions. CAR has been shown to be highly expressed in lung cancer where it is proposed to promote tumor growth and regulate epithelial mesenchymal transition (EMT), however the potential role of CAR in lung cancer metastasis remains poorly understood. To better understand the role of this receptor in tumor progression, we manipulated CAR expression in both epithelial-like and mesenchymal-like lung cancer cells. In both cases, CAR overexpression promoted tumor growth in vivo in immunocompetent mice and increased cell adhesion in the lung after intravenous injection without altering the EMT properties of each cell line. Overexpression of WTCAR resulted in increased invasion in 3D models and enhanced β1 integrin activity in both cell lines, and this was dependent on phosphorylation of the CAR cytoplasmic tail. Furthermore, phosphorylation of CAR was enhanced by substrate stiffness in vitro, and CAR expression increased at the boundary of solid tumors in vivo. Moreover, CAR formed a complex with the focal adhesion proteins Src, Focal Adhesion Kinase (FAK) and paxillin and promoted activation of the Guanine Triphosphate (GTP)-ase Ras-related Protein 1 (Rap1), which in turn mediated enhanced integrin activation. Taken together, our data demonstrate that CAR contributes to lung cancer metastasis via promotion of cell-matrix adhesion, providing new insight into co-operation between cell-cell and cell-matrix proteins that regulate different steps of tumorigenesis.

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Section: Discussionsupporting

confidence: 94%

“…Adenovirus Type5 fiberknob (Ad5FK) was produced and purified as previously described ( 27 ). CAR thr290/ser293 polyclonal antibody was developed by Perbioscience (Thermofisher) using the peptide Ac-RTS ( 28 )AR(pS)YIGSNH-C and was affinity purified before use. DAPI (Sigma Aldrich) was used as nuclear stain for immunofluorescence.…”

Section: Methodsmentioning

confidence: 99%

CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion

et al. 2022

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“…For example, loss of CXADR expression is associated with increased epithelial-mesenchymal transition in breast cancer [ 40 ] and increased gastric cancer metastasis [ 41 ]. A similar association with decreased CXADR expression and increased malignancy was also observed in both mouse and human melanoma where CXADR expression was higher in benign lesions and during early stages of tumor growth but was decreased upon tumor growth and progression [ 38 ]. Furthermore, both mouse and human melanocytes express very low levels of CXADR suggesting that CXADR expression is linked to melanoma tumorigenesis [ 38 ].…”

Section: Introductionmentioning

confidence: 53%

“…A similar association with decreased CXADR expression and increased malignancy was also observed in both mouse and human melanoma where CXADR expression was higher in benign lesions and during early stages of tumor growth but was decreased upon tumor growth and progression [ 38 ]. Furthermore, both mouse and human melanocytes express very low levels of CXADR suggesting that CXADR expression is linked to melanoma tumorigenesis [ 38 ]. During the early stages of the disease, this pattern of CXADR expression mirrors findings in cutaneous wound healing where expression is low under homeostatic conditions but is increased following tissue damage or malignant transformation.…”

Section: Introductionmentioning

confidence: 53%

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γδ T cell costimulatory ligands in antitumor immunity

McGraw

Witherden

2022

Explor Immunol

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Antitumor immunity relies on the ability of T cells to recognize and kill tumor targets. γδ T cells are a specialized subset of T cells that predominantly localizes to non-lymphoid tissue such as the skin, gut, and lung where they are actively involved in tumor immunosurveillance. γδ T cells respond to self-stress ligands that are increased on many tumor cells, and these interactions provide costimulatory signals that promote their activation and cytotoxicity. This review will cover costimulatory molecules that are known to be critical for the function of γδ T cells with a specific focus on mouse dendritic epidermal T cells (DETC). DETC are a prototypic tissue-resident γδ T cell population with known roles in antitumor immunity and are therefore useful for identifying mechanisms that may control activation of other γδ T cell subsets within non-lymphoid tissues. This review concludes with a brief discussion on how γδ T cell costimulatory molecules can be targeted for improved cancer immunotherapy.

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Pro‐ and antitumorigenic functions of γδ T cells

Fiala,

Lücke,

Huber

2024

Eur J Immunol

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Abstractγδ T cells are a subset of T cells that are characterized by the expression of a TCR‐γδ instead of a TCR‐αβ. Despite being outnumbered by their αβ T cell counterpart in many tissues, studies from the last 20 years underline their important and non‐redundant roles in tumor and metastasis development. However, whether a γδ T cell exerts pro‐ or antitumorigenic effects seems to depend on a variety of factors, many of them still incompletely understood today. In this review, we summarize mechanisms by which γδ T cells exert these seemingly contradictory effector functions in mice and humans. Furthermore, we discuss the current view on inducing and inhibiting factors of γδ T cells during cancer development.

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JAML promotes CD8 and γδ T cell antitumor immunity and is a novel target for cancer immunotherapy

Cited by 17 publications

References 53 publications

CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion

CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion

γδ T cell costimulatory ligands in antitumor immunity

Pro‐ and antitumorigenic functions of γδ T cells

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