Preferential activation of regulatory T (Treg) cells limits autoimmune tissue damage during chronic immune responses but can also facilitate tumor growth. Here, we show that tissue-produced inflammatory mediators prime maturing dendritic cells (DC) for the differential ability of attracting anti-inflammatory Treg cells. Our data show that prostaglandin E 2 (PGE 2 ), a factor overproduced in chronic inflammation and cancer, induces stable Treg-attracting properties in maturing DC, mediated by CCL22. The elevated production of CCL22 by PGE 2 -matured DC persists after the removal of PGE 2 and is further elevated after secondary stimulation of DC in a neutral environment. This PGE 2 -induced overproduction of CCL22 and the resulting attraction of FOXP3 + Tregs are counteracted by IFNA, a mediator of acute inflammation, which also restores the ability of the PGE 2 -exposed DC to secrete the Th1-attracting chemokines: CXCL9, CXCL10, CXCL11, and CCL5. In accordance with these observations, different DCs clinically used as cancer vaccines show different Treg-recruiting abilities, with PGE 2 -matured DC, but not type 1-polarized DC, generated in the presence of type I and type II IFNs, showing high Treg-attracting activity. The current data, showing that the ability of mature DC to interact with Treg cells is predetermined at the stage of DC maturation, pave the way to preferentially target the regulatory versus proinflammatory T cells in autoimmunity and transplantation, as opposed to intracellular infections and cancer. [Cancer Res 2008;68(14):5972-8]

Tumor vaccines can induce robust immune responses targeting tumor antigens in the clinic, but antitumor effects have been disappointing. One reason for this is ineffective tumor infiltration of the cytotoxic T lymphocytes (CTLs) produced. Oncolytic viruses are capable of selectively replicating within tumor tissue and can induce a strong immune response. We therefore sought to determine whether these therapies could be rationally combined such that modulation of the tumor microenvironment by the viral therapy could help direct beneficial CTLs induced by the vaccine. As such, we examined the effects of expressing chemokines from oncolytic vaccinia virus, including CCL5 (RANTES), whose receptors are expressed on CTLs induced by different vaccines, including type-1-polarized dendritic cells (DC1). vvCCL5, an oncolytic vaccinia virus expressing CCL5, induced chemotaxis of lymphocyte populations in vitro and in vivo, and displayed improved safety in vivo. Interestingly, enhanced therapeutic benefits with vvCCL5 in vivo correlated with increased persistence of the viral agent exclusively within the tumor. When tumor-bearing mice were both vaccinated with DC1 and treated with vvCCL5 a further significant enhancement in tumor response was achieved which correlated with increased levels of tumor infiltrating lymphocytes. This approach therefore represents a novel means of combining biological therapies for cancer treatment.

The ability of cancer vaccines to induce tumor-specific CD8+ T cells in the circulation of cancer patients has been shown to poorly correlate with their clinical effectiveness. In this study, we report that although Ags presented by different types of mature dendritic cells (DCs) are similarly effective in inducing CD8+ T cell expansion, the acquisition of CTL function and peripheral-type chemokine receptors, CCR5 and CXCR3, requires Ag presentation by a select type of DCs. Both “standard” DCs (matured in the presence of PGE2) and type 1-polarized DCs (DC1s) (matured in the presence of IFNs and TLR ligands, which prevent DCs “exhaustion”) are similarly effective in inducing CD8+ T cell expansion and acquisition of CD45RO+IL-7R+IL-15R+ phenotype. However, granzyme B expression, acquisition of CTL activity, and peripheral tissue-type chemokine responsiveness are features exclusively exhibited by CD8+ T cells activated by DC1s. This advantage of DC1s was observed in polyclonally activated naive and memory CD8+ T cells and in blood-isolated melanoma-specific CTL precursors. Our data help to explain the dissociation between the ability of cancer vaccines to induce high numbers of tumor-specific CD8+ T cells in the blood of cancer patients and their ability to promote clinical responses, providing for new strategies of cancer immunotherapy.

Therapeutic cancer vaccines rely on the immune system to eliminate tumor cells. In contrast to chemotherapy or passive (adoptive) immunotherapies with antibodies or ex vivo-expanded T cells, therapeutic vaccines do not have a direct anti-tumor activity, but aim to reset patients' immune systems to achieve this goal. Recent identification of effective ways of enhancing immunogenicity of tumor-associated antigens, including the use of dendritic cells and other potent vectors of cancer vaccines, provide effective tools to induce high numbers of circulating tumor-specific T cells. However, despite indications that some of the new cancer vaccines may be able to delay tumor recurrence or prolong the survival of cancer patients, their ability to induce cancer regression remains low. Recent reports help to identify and prospectively remove the remaining obstacles towards effective therapeutic vaccination of cancer patients. They indicate that the successful induction of tumor-specific T cells by cancer vaccines is not necessarily associated with the induction of functional cytotoxic T lymphocytes, and that current cancer vaccines may promote undesirable expansion of Treg cells. Furthermore, recent studies also identify the tools to counteract such phenomena, in order to assure the desirable induction of Th1-cytotoxic T lymphocytes, NK-mediated type-1 immunity and appropriate homing of effector cells to tumors. †Author Immune system as a means to fight cancerDespite an overall progress in cancer therapy, substantial groups of cancer patients lack effective treatment options, and even larger groups lack curative therapies. Combined use of surgery, radio-and chemo-therapy is often highly active in eliminating the major tumor mass, but is less effective in eliminating residual cancer cells and in preventing disease recurrence. This particular deficit of the current treatments provides the rationale for the utilization of the immune system, specialized in eliminating such 'rare events' in our bodies as invading bacteria or the individual host's cells hijacked by viruses, in order to identify and destroy cancer cells.The goal of therapeutic cancer vaccines (or active immunotherapy) is to instruct the patient's own immune system to kill cancer cells. Compared with chemotherapy, the theoretical advantages of such an approach are its higher ability to selectively eliminate the transformed cells, resulting in low toxicity, and the ability to recognize and attack multiple target molecules, even the newly arising antigens on rapidly mutating tumor cells (due to the phenomenon of epitope spreading). 1]). Throughout the following century, repeated attempts to utilize the immune system to fight cancer in a systematic approach were met with limited success, prompting a century-long debate on the relevance of the immune system to cancer surveillance and therapy [2,3].At the beginning of the 21st century, it has become evident that the immune system can be utilized to fight cancer, but it is also clear that the spontaneously ...

In C57BL/6 (B6) mice, most herpes simplex virus (HSV)-specific CD8 T cells recognize a strongly immunodominant epitope on glycoprotein B (gB 498 ) and can inhibit HSV type 1 (HSV-1) reactivation from latency in trigeminal ganglia (TG). However, half of the CD8 T cells retained in latently infected TG of B6 mice are not gB 498 specific and have been largely ignored. The following observations from our current study indicate that these gB 498 -nonspecific CD8 T cells are HSV specific and may contribute to the control of HSV-1 latency. First, following corneal infection, OVA 257 -specific OT-1 CD8 T cells do not infiltrate the infected TG unless mice are simultaneously immunized with OVA 257 peptide, and then they are not retained. Second, 30% of CD8 T cells in acutely infected TG that produce gamma interferon in response to HSV-1 stimulation directly ex vivo are gB 498 nonspecific, and these cells maintain an activation phenotype during viral latency. Finally, gB 498 -nonspecific CD8 T cells are expanded in ex vivo cultures of latently infected TG and inhibit HSV-1 reactivation from latency in the absence of gB 498 -specific CD8 T cells. We conclude that many of the CD8 T cells that infiltrate and are retained in infected TG are HSV specific and potentially contribute to maintenance of HSV-1 latency. Identification of the viral proteins recognized by these cells will contribute to a better understanding of the dynamics of HSV-1 latency.The generation and maintenance of a CD8 T-cell response represent an important line of defense against many viral pathogens. Such responses are typically initiated when host antigen-presenting cells at the site of infection capture and process viral proteins and transport them to local draining lymph nodes (DLN). There the antigen-presenting cells either directly present viral antigens to naïve CD8 T cells or pass them to a distinct LN-resident dendritic cell (DC) subset for antigen presentation in the context of major histocompatibility complex class I (1). Antigen-specific CD8 T cells then undergo robust division and differentiation into effector populations armed to infiltrate infected tissue and eliminate the invading pathogen. The magnitude of the CD8 T-cell response against different viral epitopes is typically aligned within a defined hierarchy. Those epitopes recognized by the largest portion of the pathogen-specific CD8 T-cell population are referred to as immunodominant, while those inciting lesser responses are referred to as subdominant (17). Manipulation of this hierarchal system by the elimination of an immunodominant epitope often results in the expansion of a normally silent or "cryptic" determinant (2, 17, 21).Although the HSV-1 genome contains at least 84 open reading frames (13), it is estimated that 70 to 95% of the acute CD8 T-cell response in lymphoid organs of B6 mice is directed against the single immunodominant gB 498 epitope (11,21,24,26,27). The remaining HSV-specific CD8 T cells are thought to be directed against a subdominant epitope on the viral ribonuc...