Differential CD40/CD40L Expression Results in Counteracting Antitumor Immune Responses

Abstract

Establishment of host-protective memory T cells against tumors is the objective of an antitumor immunoprophylactic strategy such as reinforcing T cell costimulation via CD40-CD40L interaction. Previous CD40-targeted strategies assumed that T cell costimulation is an all-or-none phenomenon. It was unknown whether different levels of CD40L expression induce quantitatively and qualitatively different effector T cell responses. Using mice expressing different levels of CD40L, we demonstrated that the greater the T cell CD40L expression the less tumor growth occurred; the antitumor T cell response was host-protective. Lower levels of CD40L expression on T cells induced IL-10-mediated suppression of tumor-regressing effector CD8+ T cells and higher productions of IL-4 and IL-10. Using mice expressing different levels of CD40 or by administering different doses of anti-CD40 Ab, similar observations were recorded implying that the induction of protumor or antitumor T cell responses was a function of the extent of CD40 cross-linking. IL-10 neutralization during priming with tumor Ags resulted in a stronger tumor-regressing effector T cell response. Using IL-10−/− DC for priming of mice expressing different levels of CD40L and subsequent transfer of the T cells from the primed mice to nu/nu mice, we demonstrated the protumor role of IL-10 in the induction of tumor-promoting T cells. Our results demonstrate that a dose-dependent cross-linking of a costimulatory molecule dictates the functional phenotype of the elicited effector T cell response. The T cell costimulation is a continuum of a function that induces not only graded T cell responses but also two counteracting responses at two extremes.

CD40 ligand‐expressing recombinant vaccinia virus promotes the generation of CD8+ central memory T cells

“…In contrast, following 24 h infection with VV-WT or rVV40L, lower, nonsignificant increases of CD80 and PD-L1 levels were detected on treated monocytes. Figure 2B shows data from one representative experiment and summarizes the results obtained in three independent assays.Notably, CD1a induction, suggestive of a dendritic cell differentiation was undetectable in all culture conditions (data not shown).Taken together, these data underline the different biological properties of membrane-bound CD40L, as provided by a rVV40L controlled infection, as compared to its soluble form, possibly reflecting a differential cross-linking of CD40 receptor expressed on the surfaces of CD14 + monocytes [24,[26][27][28]. …”

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

“…We have shown that CD40 engagement by CD40L expressed by a tumor-cell vaccine can increase immunity against tumor antigens cross-presented by DCs [27] and that the CD40/CD40L axis is required for CTL induction by vaccination with GM-CSF/OX40L-transduced tumor cells [65]. T cells expressing high levels, but not low or null levels, of CD40L can adoptively transfer an efficient anti-tumor immunity [19]. We propose here that OX40 triggering can indirectly enhance CD40 stimulation to tumor-infiltrating DCs by increasing CD40L expression by tumor-infiltrating Tem cells, otherwise kept in a quiescent state.…”

“…The CD40/CD40L interaction is crucial for DC activation, survival and proliferation [26]. Many data suggest that this axis is involved in inducing protective anti-tumor immune response [18,19,27,28] and that activation of this pathway may represent a strategy for tumor treatment. To investigate whether OX86-induced tumor rejection was dependent on the CD40/CD40L axis, WT and CD40 À/À mice were inoculated subcutaneously with CT26 cells and treated intratumorally with OX86.…”

“…The CD40/CD40L axis is crucial for DC maturation and the subsequent T-cell priming. However in the tumor microenvironment this costimulatory pathway is often dampened, thus impairing the generation of an efficient anti-tumor immune response [18,19].In this study we have investigated the mechanisms by which OX86 modulates Treg-and Teff-cell functions and their reciprocal interactions with DCs at the tumor site. We propose a model of the tumor microenvironment in which, after OX86 treatment, DCs receive a lower IL-10-mediated inhibition by Treg cells on the one hand, and a stronger stimulation from Tem cells, via the CD40/CD40L axis, on the other.…”

“…The CD40/CD40L axis is crucial for DC maturation and the subsequent T-cell priming. However in the tumor microenvironment this costimulatory pathway is often dampened, thus impairing the generation of an efficient anti-tumor immune response [18,19].…”