Co-expression of CD40L with CD70 or OX40L increases B-cell viability and antitumor efficacy

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.

HBcAg‐induced upregulated 4‐1BB ligand on B cells contributes to B‐cell hyperactivation during chronic hepatitis B infection

“…Meanwhile, the productions of IFN‐γ and TNF‐α were downregulated in the 4‐1BBL+ B cell group, indicating a negative regulatory role for cellular immunity. Interestingly, our data were not consistent with other studies, in which 4‐1BBL+ B cells could induce GrB+ CD8+ T cells and increase the proliferation of antigen‐specific CD8+ T cells . However, in our study, the 4‐1BBL+ B cells could increase cytokine secretion of IL‐2, IL‐4, and IL‐6.…”

“…Interestingly, our data were not consistent with other studies, in which 4-1BBL+ B cells could induce GrB+ CD8+ T cells and increase the proliferation of antigen-specific CD8+ T cells. 17,37 However, in our study,…”

T Cells Modified with CD70 as an Alternative Cellular Vaccine for Antitumor Immunity

“…It has been reported that PD-L1 is widely expressed on APCs such as macrophages, DCs, and B cells, and upregulated in response to inflammatory stimuli [27]. We and other have also shown that PD-1/PD-L1 blockade prevents exhaustion of tumor-reactive T cells in several malignancies, augmenting effector function and longevity of antigen-specific T cells at the tumor site [8,28,29]. A previous report demonstrated PD-L1 expression on murine bone marrow-derived DCs and that blockade of PD-1/PD-L1 interaction enhanced the number of T cells infiltrating the tumor and augmented longevity of tumor-reactive T cells in vivo [30].…”

“…For some time, numerous groups including us have explored to identify reliable autologous APC sources as an alternative for DC-based immunotherapy. Several studies have demonstrated that ex vivo –activated B cells using inflammatory cytokines, CD40L, and Toll-like receptor ligands possess a great ability to prime and expand antigen-specific T cells, resulting in in vivo therapeutic antitumor immunity [ 8 - 10 ]. In other reports, B cells genetically modified to express the costimulatory molecules, and B cells loaded with α-galactosylceramide have synergistically amplified T-cell proliferation as efficiently as DCs in vitro and induced a wide range of adaptive immunity against tumor cells [ 11 , 12 ].…”

Trial Watch: Immunostimulatory monoclonal antibodies for oncological indications

“…[67][68][69][70][71] The most relevant receptors in this setting are CD27, [72][73][74] CD28, [75][76][77] CD40, [78][79][80][81][82] TNF receptor superfamily, member 4 (TNFRSF4; best known as OX40), [83][84][85] TNF receptor superfamily member 9 (TNFRSF9; best known as CD137 or 4-1BB), [86][87][88][89] TNF receptor superfamily member 18 (TNFRSF18; best known as GITR), [90][91][92] and inducible T-cell costimulatory (ICOS). [93][94][95][96][97] The natural ligand for CD27 is CD70, 74,[98][99][100][101][102] CD28 is activated by CD80 and CD86 (hence sharing ligand specificity with CTLA4), 41,[103][104][105][106] while CD40 is the receptor for CD40 ligand (CD40LG), [107][108][109] OX40 for TNF superfamily member 4 (TNFSF4; best known as OX40L), [110]…”