PD-L1/PD-1 blocking antibodies have demonstrated therapeutic efficacy across a range of human cancers. Extending this benefit to a greater number of patients, however, will require a better understanding of how these therapies instigate anticancer immunity. Although the PD-L1/PD-1 axis is typically associated with T cell function, we demonstrate here that dendritic cells (DCs) are an important target of PD-L1 blocking antibody. PD-L1 binds two receptors, PD-1 and B7.1 (CD80). PD-L1 is expressed much more abundantly than B7.1 on peripheral and tumor-associated DCs in patients with cancer. Blocking PD-L1 on DCs relieves B7.1 sequestration in cis by PD-L1, which allows the B7.1/CD28 interaction to enhance T cell priming. In line with this, in patients with renal cell carcinoma or non–small cell lung cancer treated with atezolizumab (PD-L1 blockade), a DC gene signature is strongly associated with improved overall survival. These data suggest that PD-L1 blockade reinvigorates DC function to generate potent anticancer T cell immunity.

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...

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Purpose: Blockade of CTLA-4 by antibodies has potentiated antitumor T-cell responses in both preclinical models and clinical trials. However, treatment with CTLA-4 blocking antibodies is associated with autoimmune and inflammatory side effects. In this study, we propose a novel administration method for CTLA-4 blocking antibodies as monotherapy.Experimental Design: We use different preclinical mouse models of cancer to investigate the local administration of CTLA-4 blocking antibody and its effect on cancer progression and the antitumor T-cell response.Results: By injecting the antibodies in a subcutaneous slow-release delivery formulation in the tumor area, we show that an eight-fold lower dose of antibody is as effective in inducing tumor eradication as systemic delivery. A lower dose and slow release of the antibody results in thousand-fold decreased levels of antibody in the serum, reducing adverse events and the risk of autoimmunity. The main target and effector cells of the CTLA-4 blockade treatment in the studied tumor models are tumor-specific endogenous CD8 þ T cells that are capable of eradicating also distant tumors, whereas CD4 þ T cells do not play a prominent role in the antibody-mediated tumor eradication. Conclusions: Injecting CTLA-4 blocking antibody in a slow-release formulation close to the tumor is an effective way of activating the antitumor T-cell response. This administration method is associated with very low serum levels of antibody, which decreases the risk of treatment-induced side effects. These results call for exploration of a similar delivery principle in clinical settings.