The CD70/CD27 Pathway Is Critical for Stimulation of an Effective Cytotoxic T Cell Response against B Cell Precursor Acute Lymphoblastic Leukemia

Abstract

For effective immunotherapy, maintaining the frequency and cytotoxic potential of effector cells is critical. In this context costimulation via the CD70/CD27 pathway has been proven essential. CD70 has been reported to be expressed to varying degrees on malignant B cells. However, in B cell precursor acute lymphboblastic leukemia, the most common childhood malignancy, the role of CD70 in stimulation of antileukemic T cell responses has so far not been delineated. Herein we demonstrate that in B cell precursor acute lymphboblastic leukemia expression of CD70 is low but can be induced upon blast activation via CD40. Both CD70 and CD80/CD86 up-regulated on CD40-stimulated blasts contribute to primary stimulation of T cell proliferation and cytokine production in an additive manner. These two signals also cooperate in the prevention of T cell anergy. In contrast to blockade of CD70 during the effector phase, inhibition of CD70-mediated costimulation during generation of antileukemic T cells prevents effector cell proliferation and reduces their cytotoxic capacity. Modulation of the CD70/CD27 pathway may thus represent a novel therapeutic approach for augmenting magnitude and quality of the antileukemic response in B cell precursor acute lymphboblastic leukemia.

CD70: An emerging target in cancer immunotherapy

“…Nevertheless, expression of CD70 on tumor cells or antigenpresenting cells has also been described to have anti-tumoral effects (Arens et al, 2004;Bak et al, 2012;Couderc et al, 1998;Glouchkova et al, 2009;Kelly et al, 2002;Lorenz et al, 1999). This raises the question if CD70 blocking antibodies might also have the opposite effect on anti-tumoral immunity by blocking the stimulatory function of CD70 on antigen-presenting cells and NK cells or by depleting activated T cells, as suggested by the CD27-agonistic antibody, CDX-1127 (Thomas et al, 2014).…”

Searching for “signal 2”: costimulation requirements of γδ T cells

“…Consistent with this, work on CD8 ? T cells has demonstrated that the expansion of tumourspecific cytotoxic T lymphocytes (CTLs) is critically dependent on CD27 costimulation [63,64].…”

Soluble CD27-Pool in Humans May Contribute to T Cell Activation and Tumor Immunity

“…However, another soluble molecule belonging to the same TNF family, soluble CD40L (sCD40L), has been previously investigated and has been shown to play a costimulatory role in immune activation and regulation (12, 13). A recent study showed that a soluble form of CD27 (sCD27) shed by Waldenström's macroglobulinemia (WM) lymphoplasmacytic cells mediated up-regulation of CD40L and a proliferation-inducing ligand (APRIL) on WM mast cells (14), suggesting that sCD27 may act agonistically in the process of immune activation. This agonistic effect may help to break immunological tolerance of tumors.…”