Co-expression of CD40L with CD70 or OX40L increases B-cell viability and antitumor efficacy
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Chang-Ae Shin1, Hyun-Woo Cho1, A-Ri Shin2,3, Hyun-Jung Sohn2, Hyun-Il Cho2,3, Tai-Gyu Kim1,2,3
1Department of Microbiology and Immunology, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea
2Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea
3Catholic Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 137-701, South Korea
Hyun-Il Cho, email: [email protected]
Tai-Gyu Kim, email: [email protected]
Keywords: cancer vaccine, B-cells, costimulatory ligand, anti-apoptosis, tumor immunity
Received: February 24, 2016 Accepted: May 29, 2016 Published: June 15, 2016
Activated B-cells are a promising alternative source of antigen-presenting cells. They can generally be obtained in sufficient numbers for clinical use, but in most instances produce weak immune responses and therapeutic effects that are suboptimal for use in therapeutic cancer vaccines. To improve the immunogenic potency and therapeutic efficacy of B-cell-based vaccines, ex vivo-activated B-cells were transduced with recombinant lentiviruses in order to express additional costimulatory ligands—CD40L, CD70, OX40L, or 4-1BBL—either individually or in pairs (CD70/CD40L, OX40L/CD40L, or 4-1BBL/CD40L). We observed that the expression of CD40L molecules on B-cells was crucial for T-cell priming and activation. Administration of B-cells co-expressing CD40L with the other costimulatory ligands provided substantial antigen-specific CD8 T-cell responses capable of provoking in vivo proliferation and potent cytolytic activities. Notably, expression of CD40L augmented B-cell viability by inhibiting apoptosis through upregulated expression of the anti-apoptotic molecules BCL2, Bcl-xL and Bax. B-cells co-expressing CD40L with CD70, OX40L, or 4-1BBL induced potent therapeutic antitumor effects in a B16 melanoma model. Moreover, the combination of genetically-modified B-cell vaccines with programmed cell death-1 blockade potentiated the therapeutic efficacy. These results suggest that B-cells endowed with additional costimulatory ligands enable the design of effective vaccination strategies against cancer.
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