Abstract
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.
Highlights
Since cytotoxic CD8 T-cells are key immune effectors that eradicate malignant cells, a prerequisite for cancer immunotherapy is to activate and expand tumor-reactive CD8 T-cells capable of recognizing and destroying tumor cells [1, 2]
CD40-activated B-cells had insignificant expression of costimulatory molecules CD80, CD40L, CD70, OX40L, and 4-1BBL, which was unaffected after lentiviral transduction (Figure 1E)
The mice that received B-cells co-expressing CD40L together with other costimulatory ligands (CD70/CD40L-B, OX40L/ CD40L-B, and 4-1BBL/CD40L-B) had significantly higher levels of Trp2180-specific CD8 T-cell responses than those receiving other conditioned B-cell vaccinations. These results indicate that B-cells genetically modified to express additional costimulatory ligands CD70, OX40L, and 4-1BBL exhibit augmented antigen-presenting cells (APCs) function, and additional expression of CD40L enhances their ability to stimulate antigen-specific T-cells in vivo
Summary
Since cytotoxic CD8 T-cells are key immune effectors that eradicate malignant cells, a prerequisite for cancer immunotherapy is to activate and expand tumor-reactive CD8 T-cells capable of recognizing and destroying tumor cells [1, 2]. The activation of CD8 T-cells requires additional costimulatory signals offered by antigen-presenting cells (APCs) such as dendritic cells (DCs), along with the engagement of T-cell receptors (TCRs) with cognate peptide-major histocompatibility complex (pMHC) class-I molecules [3]. Mature DCs, which express high levels of MHC molecules and costimulatory ligands, have been shown to be efficient cellular adjuvants that evoke and augment tumor-reactive CD8 T-cell responses both in vitro and in vivo [4, 5]. DCs genetically modified to express immunestimulatory molecules, such as costimulatory ligands and cytokines, have elicited enhanced T-cell responses in vitro and in vivo [6, 7]. DC-based cellular vaccines have been shown to be safe and apparently immunogenic in cancer patients, no significant protective immunity has been achieved
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