Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that is implicated in suppressing T-cell immunity in normal and pathologic settings. Here, we describe that spontaneous cytotoxic T-cell reactivity against IDO exists not only in patients with cancer but also in healthy persons. We show that the presence of such IDO-specific CD8 ؉ T cells boosted T-cell immunity against viral or tumor-associated antigens by eliminating IDO ؉ suppressive cells. This had profound effects on the balance between interleukin-17 (IL-17)-producing CD4 ؉ T cells and regulatory T cells. Furthermore, this caused an increase in the production of the proinflammatory cytokines IL-6 and tumor necrosis factor-␣ while decreasing the IL-10 production. Finally, the addition of IDO-inducing agents (ie, the TLR9 ligand cytosinephosphate-guanosine, soluble cytotoxic T lymphocyte-associated antigen 4, or interferon ␥) induced IDO-specific T cells among peripheral blood mononuclear cells from patients with cancer as well as healthy donors. In the clinical setting, IDO may serve as an important and widely applicable target for immunotherapeutic strategies in which IDO plays a significant regulatory role. We describe for the first time effector T cells with a general regulatory function that may play a vital role for the mounting or maintaining of an effective adaptive immune response. We suggest terming such effector T cells "supporter T cells." (Blood. 2011;117(7): 2200-2210) IntroductionInduction of tolerance, which is a central mechanism counteracting tumor-specific immunity and preventing effective anticancer immune therapy, requires a specific environment in which tolerogenic dendritic cells (DCs) play an essential role deviating the immune response away from effective immunity. It was recently shown that IDO provides a potential mechanism for the development of DC-mediated T-cell tolerance. IDO ϩ DCs inhibit T-cell proliferation because of tryptophan depletion and accumulation of toxic tryptophan metabolites. 1,2 IDO ϩ DCs have been shown to induce T-cell anergy or generation of regulatory T cells (Tregs). In patients with cancer, IDO elevation occurs in a subset of plasmacytoid DCs in tumor-draining lymph nodes. 3 In addition, most human tumors overexpress IDO. 4 Activation of IDO in either tumor cells or nodal regulatory DCs each appears to be sufficient to facilitate tumoral immune escape. 2 IDO may help in tilting the tumor microenvironment from hostile to supportive for tumor cells and also may elaborate a peripheral mechanism of immune escape that could facilitate tumor progression. 5,6 Tregs have been defined as a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens. 7,8 Subsequently, they are additionally termed suppressor T cells. Tregs exist to down-regulate immune responses in various inflammatory circumstances and ultimately assure peripheral T-cell tolerance. The best-characterized subset of these immune sup...

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BackgroundThe enzyme indoleamine 2,3-dioxygenase (IDO) exerts an well established immunosuppressive function in cancer. IDO is expressed within the tumor itself as well as in antigen-presenting cells in tumor-draining lymph nodes, where it promotes the establishment of peripheral immune tolerance to tumor antigens. In the present study, we tested the notion whether IDO itself may be subject to immune responses.Methods and FindingsThe presence of naturally occurring IDO-specific CD8 T cells in cancer patients was determined by MHC/peptide stainings as well as ELISPOT. Antigen specific cytotoxic T lymphocytes (CTL) from the peripheral blood of cancer patients were cloned and expanded. The functional capacity of the established CTL clones was examined by chrome release assays. The study unveiled spontaneous cytotoxic T-cell reactivity against IDO in peripheral blood as well as in the tumor microenvironment of different cancer patients. We demonstrate that these IDO reactive T cells are indeed peptide specific, cytotoxic effector cells. Hence, IDO reactive T cells are able to recognize and kill tumor cells including directly isolated AML blasts as well as IDO-expressing dendritic cells, i.e. one of the major immune suppressive cell populations.ConclusionIDO may serve as an important and widely applicable target for anti-cancer immunotherapeutic strategies. Furthermore, as emerging evidence suggests that IDO constitutes a significant counter-regulatory mechanism induced by pro-inflammatory signals, IDO-based immunotherapy holds the promise to boost anti-cancer immunotherapy in general.

Several lines of data have suggested a possible link between the indoleamine 2,3-dioxygenase (IDO)-like protein IDO2 and cancer. First, IDO2 expression has been described in human tumors, including renal, gastric, colon, and pancreatic tumors. Second, the apparent selective inhibition of IDO2 by the D stereoisomer of the IDO blocker 1-methyl-tryptophan (1MT), which tends to be more active than the L-isomer in a variety of biological assays for IDO function, suggests that IDO2 may be important to sustain immune escape and growth of tumors. Especially, D-1MT heightens chemotherapeutic efficacy in mouse models of cancer in a nontoxic fashion. Here, we describe the immunogenicity of IDO2 by showing the presence of spontaneous cytotoxic T-cell reactivity against IDO2 in peripheral blood of both healthy donors and cancer patients. Furthermore, we show that these IDO2-specific T cells are cytotoxic effector cells that recognize and kill tumor cells. Our data suggest that IDO2 might be a useful target for anticancer immunotherapeutic strategies. Cancer Res; 71(6); 2038-44. Ó2011 AACR.

Harnessing of the immune system by the development of 'therapeutic' vaccines, for the battle against cancer has been the focus of tremendous research eVorts over the past two decades. As an illustration of the impressive amounts of data gathered over the past years, numerous antigens expressed on the surface of cancer cells, have been characterized. To this end, recent years research has focussed on characterization of antigens that play an important role for the growth and survival of cancer cells. Antiapoptotic molecules like survivin that enhance the survival of cancer cells and facilitate their escape from cytotoxic therapies represent prime vaccination candidates. The characterization of a high number of tumor antigens allow the concurrent or serial immunological targeting of diVerent proteins associated with such cancer traits. Moreover, while vaccination in itself is a promising new approach to Wght cancer, the combination with additional therapy could create a number of synergistic eVects. Herein we discuss the possibilities and prospects of vaccination when combined with other treatments. In this regard, cell death upon drug exposure may be immunogenic or non-immunogenic depending on the speciWc chemotherapeutics. Also, chemotherapy represents one of several options available for clearance of CD4 + Foxp3 + regulatory T cells. Moreover, therapies based on monoclonal antibodies may have synergistic potential in combination with vaccination, both when used for targeting of tumor cells and endothelial cells. The eYcacy of therapeutic vaccination against cancer will over the next few years be studied in settings taking advantage of strategies in which vaccination is combined with other treatment modalities. These combinations should be based on current knowledge not only regarding the biology of the cancer cell per se, but also considering how treatment may inXuence the malignant cell population as well as the immune system.

Human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, is an attractive target antigen for cancer immunotherapy due to its expression in the vast majority of human tumors. The first immunogenic peptide described from hTERT was the HLA-A2^restricted peptide hTERT540 (ILAKFLHWL). However, much discrepancy exists about the processing and presentation of this epitope on the surface of neoplastic cells. Originally, it was described that specific CTL can be generated in vitro and that such cells are able to kill a range of hTERT + tumor cell lines and primary tumors in a peptide-specific, HLA-A2^restricted fashion. Furthermore, it was described that vaccination of cancer patients with hTERT540 introduced functional antitumor CD8 + Tcells in patients. More recently, it was described that most patients with cancer have circulating hTERT540-specific CD8 + T lymphocytes. In contrast, several other studies have concluded that hTERT540 is not presented on the surface of tumor cells and that immunization of cancer patients with hTERT540 leads to the introduction of specificTcells that do not recognize tumor cells in vivo. In the present commentary, we summarize these highly contradictive results about this potentially very importantT-cell epitope. Furthermore, we describe novel data showing that naturally occurring immune responses against hTERT540 are, although rare, present in cancer patients and that such hTERT540-specificTcells are able to recognize and kill cancer cells. Hence, our data support the findings that hTERT540 peptide is presented by human tumors and can be a target for CTL-mediated tumor lysis.

Among the relatively large number of known tumor-associated antigens (TAA) which are recognized by human CD8 T-cells, Melan-A/MART-1 is one of the most-if not the most-frequently used target for anti-cancer vaccines in HLA-A2 + melanoma patients. In this study, we analyzed the killing of a large panel of melanoma cells by a high avidity, MART-1-specific T-cell clone or a MART-1-specific, polyclonal T-cell culture. Strikingly, we observed that the MART-1-specific T-cells only killed around half of the analyzed melanoma cell lines. In contrast a Bcl-2-specific T-cell clone killed all melanoma cell lines, although the T-cell avidity of this clone was significantly lower. The MART-1-specific T-cell clone expressed NKG-2D and was fully capable of releasing both perforin and Granzyme B. Notably, the resistance to killing by the MART-1-specific T-cells could be overcome by pulsing of the melanoma cells with the MART-1 epitope. Thus, the very frequently used MART-1 epitope was not expressed on the surface of many melanoma cell lines. Our data emphasize that the selected tumor antigens and/or epitopes are critical for the outcome of anti-cancer immunotherapy.

Most cancer deaths are due to the development of metastases. Increased expression of RhoC is linked to enhanced metastatic potential in multiple cancers. Consequently, the RhoC protein is an attractive target for drug design. The clinical application of immunotherapy against cancer is rapidly moving forward in multiple areas, including the adoptive transfer of anti-tumor-reactive T cells and the use of "therapeutic" vaccines. The over-expression of RhoC in cancer and the fact that immune escape by down regulation or loss of expression of this protein would reduce the morbidity and mortality of cancer makes RhoC a very attractive target for anti-cancer immunotherapy. Herein, we describe an HLA-A3 restricted epitope from RhoC, which is recognized by cytotoxic T cells. Moreover, RhoC-speciWc T cells show cytotoxic potential against HLA-matched cancer cells of diVerent origin. Thus, RhoC may serve as an important and widely applicable target for anti-cancer immunotherapeutic strategies.