Simultaneous Targeting of CD3 on T Cells and CD40 on B or Dendritic Cells Augments the Antitumor Reactivity of Tumor-Primed Lymph Node Cells

Abstract

To date, molecular targets chosen for Ab activation to generate antitumor effector cells have been confined on T cells, such as TCR/CD3, CD28, CD137 (4-1BB), CD134 (OX40), and inducible costimulator. In this report we investigated the immune function of murine tumor-draining lymph node (TDLN) cells after simultaneous Ab targeting of CD3 on T cells and CD40 on APCs. Anti-CD3 plus anti-CD40-activated TDLN cells secreted significantly higher amounts of IFN-γ, but less IL-10, compared with anti-CD3-activated cells. In adoptive immunotherapy, ligation of CD3 and CD40 resulted in the generation of more potent effector cells in mediating tumor regression. Freshly harvested TDLN cells were composed of ∼60% CD3+ T cells, 30–35% CD19+ B cells, 5% CD11c+ dendritic cells (DC), and few CD14+ or NK cells (each <3%). CD40 was distributed predominantly on B cells and DCs. Cell depletion indicated that simultaneous targeting was toward CD3 on T cells and CD40 on APCs, respectively. Elimination of APCs completely abrogated the augmented antitumor responses induced by anti-CD40. Either B cell or DC removal partially, but significantly, reduced the therapeutic efficacy conferred by CD40 engagement. Furthermore, the immunomodulation function of anti-CD40 was associated with its capability to increase IL-12 secretion while inhibiting IL-4 production. Our study establishes a role for CD40 expressed on B cells or DCs in the costimulation of TDLN cells. Eliciting antitumor activity via simultaneous targeting of CD3 on T cells and CD40 on APCs is relevant for the design of effective T cell-based cancer immunotherapy.

Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies

“…During the past few years, increasingly important roles of B cells in the immune system of cancer patients have been reported (12)(13)(14)(15)(16)(17)24). In this study, we describe an increased frequency of plasmablasts in MLNs compared with NMLNs, as well as in tumor versus nonmalignant tissue.…”

“…CD40 targeting of the TDLN B cells and dendritic cells, in combination with CD3 targeting of T cells, induced a strong antitumor response. However, depleting either B cells or DCs significantly diminished the antitumor response (16). This study illustrates the potential of TDLN B cells to be effective as APCs with generation of more potent effector cells for adoptive immunotherapy.…”

“…This underscores the role of B cells as APCs, which is also highlighted by the higher percentage of CD86 + B cells in MLNs. It has been demonstrated that TDLN B cells in mice can be efficient APCs (16,17). Yet, it remains to be demonstrated whether they play this role in humans with solid tumors.…”

Combined effects of klotho and soluble CD40 ligand on A549 lung cancer cells

“…cD40 ligand up-regulated expression of major histocompatibility complex class Ⅰ/Ⅱ and costimulatory molecules on the surface of Dcs, and increased interleukin (Il)-12, Il-6, Il-15 production by Dcs that can induce of cytotoxic t lymphocyte (ctl) responses (37,38). B cells activated through cD40 up-regulate surface expression of major histocompatibility complex and costimulatory molecules, produce Il-12, and exhibit potent antigen-presenting properties (39). cD40 expresses on a variety of malignant cells, and activation cD40 on these tumor cells up-regulates costimulatory molecules and then reduces immune escape of the tumor cells (17,18).…”

Genetically engineered T cells expressing a HER2-specific chimeric receptor mediate antigen-specific tumor regression

“…[1][2][3][4][5] However, several obstacles limited its application. Tumors are resistant to T cellmediated immune responses by loss of cell surface major histocompatibility complex (MHC) expression [6][7][8] and downregulated tumor antigen processing.…”