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The Balance Players of the Adaptive Immune System Mads Hald Andersen1,2

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The Balance Players of the Adaptive Immune System Mads Hald Andersen1,2 Published OnlineFirst February 13, 2018; DOI: 10.1158/0008-5472.CAN-17-3607 Cancer Perspective Research The Balance Players of the Adaptive Immune System Mads Hald Andersen1,2 Abstract Equilibrium between immune activation and suppression may Vaccination against genetically stable cells with regular HLA be necessary to maintain immune homeostasis, because proin- expression is an attractive way to directly target immunosuppres- flammatory effector T cells (defined as antiregulatory T cells) sive cells in addition to attracting proinflammatory cells into the counteract the functions of regulatory immune cells. These self- tumor microenvironment. Importantly, vaccination toward IDO reactive T cells recognize human leukocyte antigen (HLA)–restrict- or PD-L1 to potentiate such T cells have proven safe, with minimal ed epitopes derived from proteins expressed by regulatory immune toxicity in the clinical phase I trials conducted thus far. cells such as IDO, PD-L1, PD-L2, or arginase. The activation of Significance: Autoreactive effector T cells that specifically rec- such proinflammatory effector T cells offers a novel way to directly ognize regulatory cells might be useful to harness for cancer target the tumor microenvironment, potentially giving them immunotherapy to target the immune-suppressive tumor micro- considerable clinical value, especially in patients with cancer. environment. Cancer Res; 1–4. Ó2018 AACR. It was the recognition of suppressor T cells, now called regu- HLA-restricted derived epitopes, which are generated from intra- latory T cells (Treg), pioneered by Dr. Sakaguchi that highlighted cellular degraded antigens, are able to directly eliminate regula- the importance of regulatory cells in the maintenance of immu- tory immune cells (Fig. 1; ref. 3). In addition, anti-Tregs can boost nologic self-tolerance and immune homeostasis (1, 2). However, local immune activation by the secretion of effector cytokines. although a lot of attention has been given regulatory suppressive Thus, anti-Tregs may function as specific first responder helper T cells, new findings suggest that regulatory T cells may also have cells at the site of inflammation. It must be assumed that anti- effector capabilities. We recently reported that the immune system Tregs themselves are hampered by the suppressive effects of their has established a mechanism to counteract the variety of immune- targets. Thus, in immune regulatory networks, anti-Tregs may suppressive feedback signals: self-reactive, proinflammatory suppress the function of other regulatory immune cells and vice T cells that target immunosuppressive cells. Thus, we identified versa. Hence, under normal physiologic conditions equilibrium self-reactive T cells that recognize human leukocyte antigen between immune activation and suppression may be necessary to (HLA)–restricted epitopes derived from proteins, including indo- maintain immune homeostasis. The role of self-reactive effector leamine 2,3-dioxygenase (IDO; refs. 3–7) and PD-L1 (8–12), and suppressor cells in immune-regulatory networks may thus be expressed at inflammation sites in regulatory immune cells. miscellaneous. Professional antigen-presenting cells highly Because these T cells can directly react against regulatory immune express proteins such as PD-L1 and IDO, which are induced by cells, such cells were termed antiregulatory T cells (anti-Tregs; interferons expressed at inflammation sites. In fact, circulating ref. 13). Anti-Tregs may directly suppress the function of regula- IDO- or PD-L1 specific anti-Tregs are present in healthy donors, tory immune cells within immune regulatory networks as well as although detection was not as frequent as detection in patients assisting the adaptive immune response by secreting proinflam- with cancer (3, 6, 9, 10). We have further verified that interferons matory cytokines at inflammation sites. expand populations of IDO-specific T cells by demonstrating To keep the immune balance, regulatory immune cells, for that known IDO inducers (e.g., IFNg) lead to expansion of example, Tregs, different dendritic cell subtypes, myeloid-derived IDO-specific T cells among human PBMCs without additional suppressor cells, and M2 macrophages suppress or terminate stimulation (3). Likewise, we recently found that subcutaneous immune responses. This regulatory arm secures the unrespon- IFNg injections in C57 mice expand populations of PD-L1– siveness or tolerance to self-antigens. Regulatory immune cells specific T cells. If the mice were sacrificed 1 week after IFNg suppress immunity through a number of different cellular and injections, the spleens of the IFNg-treated mice showed a strong extracellular factors. In contrast, specific anti-Tregs recognizing PD-L1 –specific T-cell response. Similarly, 3 days of treating C57 mice with the allergen DNFB led to an influx (or expansion) of PD-L1-specific T cells at the inflammation site (in prep.). Further- 1Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copen- more, it has been described that the very common cytomegalo- 2 hagen University Hospital, Herlev, Denmark. Department of Immunology and virus (CMV) induces IDO expression in vivo, which has been Microbiology, University of Copenhagen, Copenhagen, Denmark. suggested to confer an advantage to CMV-infected cells, allowing Corresponding Author: Mads Hald Andersen, Herlev Hospital, Herlev Ringvej 75, them to escape T-cell responses (14). Notably, we found that the 2730 Herlev, Denmark. Phone: 453-868-2602; Fax: 454-453-0176; E-mail: presence of IDO-specific T-cell responses in the periphery was [email protected] associated with the CMV T-cell response (6). It has long been doi: 10.1158/0008-5472.CAN-17-3607 thought that self-reactive T cells harboring T-cell receptors Ó2018 American Association for Cancer Research. with high affinity to a target/human leukocyte antigen complex www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst February 13, 2018; DOI: 10.1158/0008-5472.CAN-17-3607 Andersen Figure 1. Regulatory immune cells (e.g., TAMs, MDSCs, Tregs) or cancer cells express high levels of certain proteins, for example, PD-L1, IDO, arginase, Foxp3 (red arrow), and are suppressing the function of immune effector cells in the microenvironment by several different means (red inhibitory arrow bar). These include the upregulation of inhibitory surface receptors and ligands, induction of distinct sets of metabolic enzymes or chemokines, and cytokines that recruit or modify regulatory immune cells. These molecules are transiently induced in normal tissues in response to inflammation or stress but are often hijacked by malignant cells and are constitutively expressed in various cancer tissues, where they create an immunosuppressive microenvironment and contribute to immune evasion of cancer. For example, arginase (ARG1 and ARG2) catalyzes the conversion of arginine. ARG1 is inducible in M2 macrophages, MDSCs, DCs, and granulocytes. ARG-dependent arginine depletion leads to downregulation of the TCRz chain and suppression of the proliferation of effector T cells and natural killer (NK) cells. Likewise, the expression of indoleamine 2,3-dioxygenase (IDO: IDO1 and IDO2) and tryptophan 2,3-dioxygenase (TDO) play a vital role in immune tolerance. Both IDO and TDO catalyze the degradation of the tryptophan to kynurenine. Tryptophan depletion and the accumulation of kynurenine metabolites lead to proliferative arrest of effector T cells as well as the induction and recruitment of Tregs as well as MDSCs. Furthermore, the interaction of checkpoint proteins programmed death-1 (PD-1) and its ligands PD-L1 and/or PD-L2 represent another example of an important immunosuppressive mechanism in the tumor microenvironment. Finally, induction of Treg differentiation and the recruitment, for example, by CCL22 expression, is another way in which malignant cells evade the host's immune system. Anti-Tregs are defined as specific proinflammatory T cells recognizing HLA-restricted derived epitopes, which are generated from proteins expressed by regulatory immune cells (blue arrow). Anti-Tregs react by releasing proinflammatory cytokines and/or granzymes (black arrow) in response to their cognate target cells. Hence, anti-Tregs exhibit cytotoxic activity against both target-expressing cancer cells, including melanoma, breast cancer, colon cancer, and AML as well as normal immune cells like myeloid cells and CD25hi FOXP3þ CD127À Tregs. Furthermore, anti-Tregs can indirectly augment both the effector functions as well as the proliferation of other effector cells. Hence, the activation of anti-Tregs boosts both antiviral immunity, for example, T-cell responses toward CMV or influenza antigens, as well as the response to cancer antigens like Mart-1. Under normal physiologic conditions, equilibrium between immune activation (anti-Tregs) and suppression (regulatory cells) may be necessary to maintain immune homeostasis. undergo clonal deletion to maintain self-tolerance. However, Yu as metabolic enzymes (e.g., IDO) that restrain the antitumor and colleagues (15) recently demonstrated that clonal deletion activity of antitumor-specific T cells in the tumor microenviron- prunes the T-cell repertoire but does not eliminate self-reactive T- ment. In recent years, our growing knowledge of the factors cell clones. Hence, self-peptide–specific CD8 T cells were present responsible for protecting cancer cells from immune destruction in
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