CD40 stimulation leads to effective therapy of CD40⁻tumors through induction of strong systemic cytotoxic T lymphocyte immunity

Abstract

Adequate spontaneous activation of tumor-specific T lymphocytes in tumor-bearing hosts is rare, despite the expression of tumor antigens that are potentially highly immunogenic. For example, failure of the immune system to raise competent responses against established tumors expressing the human adenovirus E1A-antigen allows this tumor to grow in immunocompetent mice. We show that systemic in vivo administration of agonistic anti-CD40 antibodies into tumor-bearing mice results in tumor eradication mediated by CD8 ؉ T cells. Treatment resulted in a strong expansion and systemic accumulation of E1A-specific CTL and depended on CD40 expression on host cells, as the tumor was CD40 ؊ , and therapy failed in CD40-deficient mice. Local intratumoral administration of anti-CD40 mAb is equally effective in licensing strong, systemic CTL immunity, resulting in the clearance of distant tumor nodules. Our data indicate that the immune response after cancerhost interactions can be directed toward competence, leading to the cure of established tumors merely by delivery of a CD40-dependent ''license to kill'' signal.M ost solid tumors express MHC class I molecules but lack costimulatory molecules essential for appropriate CTL activation (1, 2). Therefore, presentation of tumor-derived antigens by professional antigen-presenting cells (APCs) is most likely required for optimal tumor-specific T cell induction (3-6). Such activation of naïve T cells is called cross-priming and was first demonstrated by Bevan (7). As naïve T cells are thought to recirculate within the lymphoid system, cross-presentation provides the immune system with a means to detect and respond to antigens that are expressed only in the periphery.An important factor determining the outcome of immune responses is the level of antigen expressed in the periphery (8). In the case of relatively low levels of antigen, antigen is not presented at sufficient levels to activate naïve T cells. This situation is associated with ignorance of the antigen by the immune system. In the case of higher antigen-expression levels, antigen will be (cross-)presented in sufficient quantities to be detected by naïve T cells. In this case, antigen-recognition can either lead to tolerance or immunity (9, 10). The outcome of antigen recognition by naïve T cells, i.e., tolerance or immunity, is thought to be the consequence of the activation state of professional APCs that (cross-)present the antigen. This activation state is strongly influenced by inflammatory stimuli as well as the action of CD4 ϩ T helper (Th) cells.Studies on the requirement of CD4 ϩ Th cells in cross-priming of cytotoxic T lymphocytes (CTL) showed that both Th cells and CTLs must recognize antigens presented on the same APC (11,12). The interaction between Th cell and APC is sufficient to convert the APC to a state that allows priming of antigen-specific CTL (13, 14), which explains the observation that infusion of antigen-specific Th cells can rescue autoreactive CTL from deletion, resulting in CTL-mediated autoimmun...

Mini‐review: Regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross‐priming and direct priming?

“…In the Adenoviral (Ad)-antigen-bearing tumors studied by us, small numbers of tetramer + CD8 + T cells were found in the tumor-draining lymph nodes, but not elsewhere [35] and this response depended on TAP expression in the host, illustrating host APC dependence (unpublished observations). These tetramer + CD8 + T cells are incapable of tumor eradication, not because of insufficient direct tumor presentation in the lymph nodes, but because of lack of proper tumor-derived activation signals for DC.…”

“…Although this event alone causes naive CTL division, it does not necessarily establish a productive immune response. Current evidence indicates that, although a small proportion of responding T cells recognizing antigen on resting DC may survive as poised T cells in draining lymph nodes [35], most T cells in the absence of appropriate costimulatory events appear to die prematurely, causing peripheral tolerance [36][37][38]. It is indeed the normal fate of T cells recognizing (self-)-antigens on resting DC in healthy tissues to meekly respond and largely be eclipsed, causing peripheral tolerance.…”

“…A large body of evidence shows that T cells die or become anergic if they do not receive these costimulatory and survival signals from DC [25,32,35,[56][57][58][59]. This is highly proper, because this places the DC in the middle of an intricate cellular network that ensures T cell death/anergy (in non-inflammatory conditions including most tumors) or survival (in the presence of dangerous pathogens).…”

“…What we do not agree with, however, is to equate this with inefficient cross-presentation. Abundant evidence shows that many different mechanisms operate to efficiently process exogenous protein antigens from tissues, including tumors, for presentation by MHC class I molecules [17,25,26,35,56,57].…”

“…In the case of the Ad-induced tumors this was demonstrated by injecting mice, in which subcutaneous tumors and small numbers of tumor-observing tetramer + CD8 + T cells coexisted, with agonistic monoclonal antibody against CD40, a strong DC-activating signal. This led to robust expansion of tetramer + T cells in the blood, spleen and non-draining lymph nodes, as well as to CTL invasion of tumors [35]. Complete eradication of established tumors was observed in approximately 80% of the mice [35].…”