A Synthetic CD8α:MyD88 Coreceptor Enhances CD8 + T-cell Responses to Weakly Immunogenic and Lowly Expressed Tumor Antigens

T cell-based immunotherapies are a promising approach for patients with advanced cancers. However, various obstacles limit T-cell efficacy, including suboptimal T-cell receptor (TCR) activation and an immunosuppressive tumor environment. Here, we developed a fusion protein by linking CD8α and MyD88...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2017-12, Vol.77 (24), p.7049-7058
Main Authors: Kaczanowska, Sabina, Joseph, Ann Mary, Guo, Jitao, Tsai, Alexander K, Lasola, Jackline Joy, Younger, Kenisha, Zhang, Yuji, Gonzales, Cruz Velasco, Davila, Eduardo
Format: Article
Language:English
Subjects:
Antigen (tumor-associated)
Antigen presentation
Antigens
Antitumor activity
Cancer
CD8 antigen
Cell activation
Cell proliferation
Costimulator
Exhaustion
Fusion protein
Histocompatibility antigen HLA
Immunogenicity
Immunosuppression
Immunotherapy
Lymphocytes
Lymphocytes T
Macrophages
Metastases
MyD88 protein
Proteins
T cell receptors
Toll-like receptors
Tumors
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Summary:T cell-based immunotherapies are a promising approach for patients with advanced cancers. However, various obstacles limit T-cell efficacy, including suboptimal T-cell receptor (TCR) activation and an immunosuppressive tumor environment. Here, we developed a fusion protein by linking CD8α and MyD88 (CD8α:MyD88) to enhance CD8 T-cell responses to weakly immunogenic and poorly expressed tumor antigens. CD8α:MyD88-engineered T cells exhibited increased proliferation and expression of effector and costimulatory molecules in a tumor antigen-dependent manner. These effects were accompanied by elevated activation of TCR and Toll-like receptor signaling-related proteins. CD8α:MyD88-expressing T cells improved antitumor responses in mice. Enhanced antitumor activity was associated with a unique tumor cytokine/chemokine signature, improved T-cell infiltration, reduced markers of T-cell exhaustion, elevated levels of proteins associated with antigen presentation, and fewer macrophages with an immunosuppressive phenotype in tumors. Given these observations, CD8α:MyD88 represents a unique and versatile approach to help overcome immunosuppression and enhance T-cell responses to tumor antigens. .
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-17-0653