The dual role of CD6 as a therapeutic target in cancer and autoimmune disease

Gurrea-Rubio, Mikel; Fox, David A.

doi:10.3389/fmed.2022.1026521

Cited by 5 publications

(8 citation statements)

References 44 publications

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“…We demonstrated that UMCD6 increases survival and augments killing by both PBMC and isolated NK cells of both triple-negative breast cancer and prostate cancer cells xenografted into immunodeficient mice. Of particular interest from both cancer immunotherapy and autoimmunity perspectives is the demonstrated ability of UMCD6 to prevent or reverse multiple models of human autoimmune disease [ 10 ], which provides an important advantage compared to current checkpoint inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…Altogether, these results provide mechanistic support for anti-CD6 therapy as a promising mAb for cancer immunotherapy. Moreover, because UMCD6 can suppress many autoimmune syndromes by its direct effects on CD4 + T cells [ 3 – 5 , 10 ], the use of this antibody to treat human cancer could avoid the troubling autoimmune complications frequently seen with current checkpoint inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Activation of cytotoxic lymphocytes through CD6 enhances killing of cancer cells

Gurrea-Rubio,

Wu,

Amin

et al. 2024

Cancer Immunol Immunother

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Immune checkpoint inhibitors (ICIs) have demonstrated efficacy and improved survival in a growing number of cancers. Despite their success, ICIs are associated with immune-related adverse events that can interfere with their use. Therefore, safer approaches are needed. CD6, expressed by T-lymphocytes and human NK cells, engages in cell–cell interactions by binding to its ligands CD166 (ALCAM) and CD318 (CDCP1). CD6 is a target protein for regulating immune responses and is required for the development of several mouse models of autoimmunity. Interestingly, CD6 is exclusively expressed on immune cells while CD318 is strongly expressed on most cancers. Here we demonstrate that disrupting the CD6-CD318 axis with UMCD6, an anti-CD6 monoclonal antibody, prolongs survival of mice in xenograft mouse models of human breast and prostate cancer, treated with infusions of human lymphocytes. Analysis of tumor-infiltrating immune cells showed that augmentation of lymphocyte cytotoxicity by UMCD6 is due to effects of this antibody on NK, NKT and CD8 + T cells. In particular, tumor-infiltrating cytotoxic lymphocytes from UMCD6-treated mice expressed higher levels of perforin and were found in higher proportions than those from IgG-treated mice. Moreover, RNA-seq analysis of human NK-92 cells treated with UMCD6 revealed that UMCD6 up-regulates the NKG2D-DAP10 receptor complex, important in NK cell activation, as well as its downstream target PI3K. Our results now describe the phenotypic changes that occur on immune cells upon treatment with UMCD6 and further confirm that the CD6-CD318 axis can regulate the activation state of cytotoxic lymphocytes and their positioning within the tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activation of cytotoxic lymphocytes through CD6 enhances killing of cancer cells

Gurrea-Rubio,

Wu,

Amin

et al. 2024

Cancer Immunol Immunother

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“…As for CD318/CDCP1 (also known as TRASK, SIMA135, or gp140), this CD6 ligand is expressed by fibroblasts and epithelial cells with which T cells interact but not by immune cells [45]. CD318 (CDCP1) is found overexpressed by epithelial and myeloid cancer cells, where it correlates with cancer progression and metastasis initiation [49]. Very recently, biochemical and biophysical evidence support the interaction of CD6 with CD44 [43], a broad tissue distribution and multifunctional cell adhesion receptor mainly involved in hyaluronic acid recognition, the major extracellular matrix component.…”

Section: The Cd6 Receptor: Structure Function Tissue Distribution And...mentioning

confidence: 99%

CD6 and Its Interacting Partners: Newcomers to the Block of Cancer Immunotherapies

Aragón-Serrano,

Carrillo-Serradell,

Planells-Romeo

et al. 2023

IJMS

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Cancer management still requires more potent and safer treatments, of which immunomodulatory receptors on the lymphocyte surface have started to show promise in new cancer immunotherapies (e.g., CTLA-4 and PD-1). CD6 is a signal-transducing transmembrane receptor, mainly expressed by all T cells and some B and NK cell subsets, whose endogenous ligands (CD166/ALCAM, CD318/CDCP-1, Galectins 1 and 3) are overexpressed by malignant cells of different lineages. This places CD6 as a potential target for novel therapies against haematological and non-haematological malignancies. Recent experimental evidence for the role of CD6 in cancer immunotherapies is summarised in this review, dealing with diverse and innovative strategies from the classical use of monoclonal antibodies to soluble recombinant decoys or the adoptive transfer of immune cells engineered with chimeric antigen receptors.

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“…Altogether, these results provide mechanistic support for anti-CD6 therapy as a promising mAb for cancer immunotherapy. Moreover, because UMCD6 can suppress many autoimmune syndromes by its direct effects on CD4 + T cells [3][4][5]10 , the use of this antibody to treat human cancer could avoid the troubling autoimmune complications frequently seen with current checkpoint inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Activation of Cytotoxic Lymphocytes Through CD6 Enhances Killing of Cancer Cells

Gurrea-Rubio,

Wu,

Amin

et al. 2023

Preprint

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Immune checkpoint inhibitors (ICIs) have demonstrated efficacy and improved survival in a growing number of cancers. Despite their success, ICIs are associated with immune-related adverse events that can interfere with their use. Therefore, safer approaches are needed. CD6, expressed by T-lymphocytes and human NK cells, engages in cell-cell interactions by binding to its ligands CD166 (ALCAM) and CD318 (CDCP1). CD6 is a target protein for regulating immune responses and is required for the development of several mouse models of autoimmunity. Interestingly, CD6 is exclusively expressed on immune cells while CD318 is strongly expressed on most cancers. Here we demonstrate that disrupting the CD6-CD318 axis with UMCD6, an anti-CD6 monoclonal antibody, prolongs survival of mice in xenograft models of human breast and prostate cancer, treated with infusions of human lymphocytes. Analysis of tumor-infiltrating immune cells showed that augmentation of lymphocyte cytotoxicity by UMCD6 is due to effects of this antibody on NK, NKT and CD8+ T cells. Tumor-infiltrating cytotoxic lymphocytes were found in higher proportions and were activated in UMCD6-treated mice compared to controls. Similar changes in gene expression were observed by RNA-seq analysis of NK cells treated with UMCD6. Particularly, UMCD6 up-regulated the NKG2D-DAP10 complex and activated PI3K. Thus, the CD6-CD318 axis can regulate the activation state of cytotoxic lymphocytes and their positioning within the tumor microenvironment.

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The dual role of CD6 as a therapeutic target in cancer and autoimmune disease

Cited by 5 publications

References 44 publications

Activation of cytotoxic lymphocytes through CD6 enhances killing of cancer cells

Activation of cytotoxic lymphocytes through CD6 enhances killing of cancer cells

CD6 and Its Interacting Partners: Newcomers to the Block of Cancer Immunotherapies

Activation of Cytotoxic Lymphocytes Through CD6 Enhances Killing of Cancer Cells

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