Cytokine-Mediated Disruption of Lymphocyte Trafficking, Hemopoiesis, and Induction of Lymphopenia, Anemia, and Thrombocytopenia in Anti-CD137-Treated Mice

Abstract

CD137-mediated signals costimulate T cells and protect them from activation-induced apoptosis; they induce curative antitumor immunity and enhance antiviral immune responses in mice. In contrast, anti-CD137 agonistic mAbs can suppress T-dependent humoral immunity and reverse the course of established autoimmune disease. These results have provided a rationale for assessing the therapeutic potential of CD137 ligands in human clinical trials. In this study, we report that a single 200-μg injection of anti-CD137 given to otherwise naive BALB/c or C57BL/6 mice led to the development of a series of immunological anomalies. These included splenomegaly, lymphadenopathy, hepatomegaly, multifocal hepatitis, anemia, altered trafficking of B cells and CD8 T cells, loss of NK cells, and a 10-fold increase in bone marrow (BM) cells bearing the phenotype of hemopoietic stem cells. These events were dependent on CD8 T cells, TNF-α, IFN-γ, and type I IFNs. BM cells up-regulated Fas, and there was a significant increase in the number of CD8+ T cells that correlated with a loss of CD19+ and Ab-secreting cells in the BM. TCR Vαβ usage was random and polyclonal among liver-infiltrating CD8 T cells, and multifocal CD8+ T cell infiltrates were resolved upon termination of anti-CD137 treatment. Anti-CD137-treated mice developed lymphopenia, thrombocytopenia, and anemia, and had lowered levels of hemoglobin and increased numbers of reticulocytes.

Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

“…The effects in the combination arms, which included liver mixed cell infiltration and single-cell necrosis with associated increases in plasma liver enzymes, splenic lymphoid hyperplasia and extramedulary hematopoiesis, and decreases in peripheral white blood cell subsets and platelets, were driven predominantly by the anti-4-1BB antibody. These findings were observed with similar severity in the anti-4-1BB-alone treatment arms and have been described previously with another mouse-reactive anti-4-1BB (44). The human relevance of the mouse findings is apparent in a previous report listing neutropenia and transaminitis as two of the most common adverse events in a phase I trial of a 4-1BB agonist antibody in patients with cancer (45).…”

CD137 ligand‐mediated reverse signals increase cell viability and cytokine expression in murine myeloid cells: Involvement of mTOR/p70S6 kinase and Akt

“…Reverse signals of CD137L enhances DC maturation and subsequent antigen-specific T-cell differentiation [36]. These together with previous studies using transgenic mice, knockout mice or mice injected with anti-CD137L Ab [19,37,38] clearly show potential in vivo effects of CD137L on innate immunity, although there are some discrepancies in the effects of CD137L. CD137L reverse signals might induce negative or positive effects on innate immunity depending on the cell CD137/CD137L are expressed and the differentiation state of that cell as suggested by Lee et al [33].…”

Immunotherapy of Cancer with 4-1BB

“…Anti-4-1BB therapy severely affects B-cell numbers and function, resulting in damping of overall humoral immunity such that autoantibody production is inhibited (13). The basis of this effect is not clear, but it is suspected that B cells are susceptible to stand-alone anti-4-1BB mAb treatment even in the absence of antigen stimulation (14). Sun and colleagues (12) showed that much of the loss of B-cell function during anti-4-1BB mAb treatment of lupus-prone mice is prevented if in vivo IFN-g is neutralized.…”

“…Further studies uncovered the existence of an increased proportion of tumor antigen-specific CD8þ T cells in the GM-CSF/anti-4-1BB-treated mice. Chronic anti-4-1BB therapy is known to deplete CD4þ T cells (14), and this effect was found to be useful for treating autoimmune diseases (4). Choi and colleagues (47) showed a beneficial effect of CD4þ T-cell depletion on anti-4-1BB-mediated antitumor activity.…”