In Situ Regulation of DC Subsets and T Cells Mediates Tumor Regression in Mice

An implanted copolymer matrix that incorporates inflammatory cytokines, an immune danger signal, and tumor antigens elicits an immune response network that can eradicate established tumors in mice. Forcing Cancer to Retreat It was a momentous moment in medical history when the English doctor Edward Jenner inoculated a young boy with cowpox, thus preventing him from catching smallpox and heralding the arrival of an era in which many infectious diseases are routinely prevented by vaccination. Today, scientists are striving to design vaccines to treat cancer—a much more complex biological challenge—by enhancing the body’s immune response against tumor cells. One critical problem is that tumors actively inhibit the immune response: They secrete factors that suppress the immune system and induce regulatory T cells that restrain the activity of tumor-fighting immune cells. Now, Mooney and colleagues describe an anticancer vaccine that triggers a sustained antitumor immune response and inhibits regulatory T cell activity—and shows promising results in mice with cancer. Key to many immune-based approaches to cancer therapy, dendritic cells survey the body for pathogens and activate immune responses against them. When immature dendritic cells recognize the molecular features characteristic of some pathogens, like DNA rich in guanosine and cytosine, the cells mature, migrate to lymph nodes, and activate T cells that recognize antigens presented on the dendritic cell surface. One approach to cancer vaccine production is to isolate dendritic precursor cells from the patient’s blood, to use in vitro treatments to convert them to dendritic cells, and then to expose them to tumor antigens. The cells are then infused back into the patient so that they will induce tumor-directed immune attack. Although responses occur, in general the vaccines do not increase the patients’ survival time relative to standard treatments or cause solid tumors to regress. A more effective cancer vaccine might require the induction of more than one class of dendritic cells, because different dendritic cell populations have different specialties, such as antigen presentation and the production of cytokines that control regulatory T cell activity. Mooney’s group aimed to generate a varied population of dendritic cells by creating a device that imitates an infection site in the host itself. Previously, they developed an implantable polymer matrix that releases an inflammatory cytokine to recruit dendritic cells and displays short strands of pathogen-like DNA and tumor antigens to activate those cells. In the present work, these researchers showed that implanting this system in mice leads to the activation of multiple dendritic cell types and the generation of tumor-fighting cytotoxic T cells, as well as to the inhibition of regulatory T cell activity. The multiple components of the system have different and synergistic effects on the host’s immune system. Notably, when used as a vaccine in mice with established melanoma, it caused complete remission of tumors and long-term survival of a substantial portion of the population. This system, which has practical advantages over approaches in which the patient’s cells are cultured, may serve as a paradigm for the design of human vaccines. Vaccines are largely ineffective for patients with established cancer, as advanced disease requires potent and sustained activation of CD8+ cytotoxic T lymphocytes (CTLs) to kill tumor cells and clear the disease. Recent studies have found that subsets of dendritic cells (DCs) specialize in antigen cross-presentation and in the production of cytokines, which regulate both CTLs and T regulatory (Treg) cells that shut down effector T cell responses. Here, we addressed the hypothesis that coordinated regulation of a DC network, and plasmacytoid DCs (pDCs) and CD8+ DCs in particular, could enhance host immunity in mice. We used functionalized biomaterials incorporating various combinations of an inflammatory cytokine, immune danger signal, and tumor lysates to control the activation and localization of host DC populations in situ. The numbers of pDCs and CD8+ DCs, and the endogenous production of interleukin-12, all correlated strongly with the magnitude of protective antitumor immunity and the generation of potent CD8+ CTLs. Vaccination by this method maintained local and systemic CTL responses for extended periods while inhibiting FoxP3 Treg activity during antigen clearance, resulting in complete regression of distant and established melanoma tumors. The efficacy of this vaccine as a monotherapy against large invasive tumors may be a result of the local activity of pDCs and CD8+ DCs induced by persistent danger and antigen signaling at the vaccine site. These results indicate that a critical pattern of DC subsets correlates with the evolution of therapeutic antitumor responses and provide a template for future vaccine design.