CD4+ CD25+ T regulatory cells, immunotherapy of cancer, and interleukin-2 (original) (raw)
Related papers
2012
Squamous cell carcinoma (SCC) constitutes a microenvironment that could modulate the antitumor immune response. Also, tumor-infiltrating lymphocytes are believed to play complex regulatory roles in antitumor immunity against SCC. The presence of regulatory T cells (Tregs) has been associated with the suppression of tumor-reactive T cells. However, the underlying mechanism for this T cell dysfunction is not clear. We used a multistage model of SCC to examine the role of Treg cells during tumor development. 7,12-dimethylbenz[a]-anthracene/phorbol 12-myristate 13-acetate treatment and systemic depletion of Treg cells using an anti-CD25 monoclonal antibody (PC61) resulted in a decrease in the number and incidence of papilloma. Furthermore, CD25 depletion increased the proportion of CD8 1 and CD4 1 T cells that were isolated from tumor lesions. The levels of interleukin (IL)-1b, IL-10, IL-12, IL-13, interferon-g, transforming growth factorb and tumor necrosis factor-a, but not IL-17, were increased in the tumor microenvironment after Treg depletion. Therefore, our results indicated involvement of CD25 1 T cells in SCC development and in the suppression of the inflammatory immune response.
Interleukin2 Mastering Regulation in Cancer and Autoimmunity
Annals of The New York Academy of Sciences, 2007
Abstract: Autoimmunity and tumor immunity evolved as two distinct arenas in immunological research. However, the identification of self-antigens as the major components of malignant cells may define a central role for autoimmunity in cancer control tuned by peripheral immunoregulatory mechanisms avoiding self-aggression. Emerging evidence documents a triple antagonistic role of interleukin-2 (IL-2) in vivo promoting survival, apoptosis, and the generation of regulatory T cells. We have found that IL-2 administration reduces the clinical course of experimental autoimmune encephalomyelitis and enhances immunoregulation in tumor-bearing mice. However, actively induced anti-IL-2 antibodies restore the response to nominal antigens in tumor-induced immunosuppressed host and induced therapeutic effect in transplantable and chemically induced tumors. It is suggested that IL-2 may contribute dynamically to the maintenance of natural immunological tolerance, preventing pathological autoimmunity, but may affect antitumor immunity. Cancer research has gained from autoimmunity understanding that tumor escape strategies include the natural mechanisms of immune tolerance and the ways to imbalance the peripheral regulatory mechanisms. Interestingly, therapeutic manipulations of immunoregulation have limited antitumor effects, although promoting collaterally infrequent autoimmune diseases. It may suggest that tumors may reinforce tolerance to protect themselves from the immune attack, a process that may involve dynamically various mechanisms including IL-2. Understanding this acquired experience from tumors may help utilize them to revert the immunopathology in autoimmune diseases.
Interleukin2Dependent Mechanisms of Tolerance and Immunity In Vivo1
2000
IL-2 is a critical T cell growth factor in vitro, but predominantly mediates tolerance in vivo. IL-2 is mainly produced by CD4 Th cells, but the role of Th cell-derived IL-2 in vivo is controversial. We demonstrate that during immunity to a tumor/self-Ag, the predominant role of Th cell-derived IL-2 was to maintain IL-2R (CD25) on CD4 T regulatory cells
Journal of immunology (Baltimore, Md. : 1950), 2018
IL-2 is critical for peripheral tolerance mediated by regulatory T (Treg) cells, which represent an obstacle for effective cancer immunotherapy. Although IL-2 is important for effector (E) T cell function, it has been hypothesized that therapies blocking IL-2 signals weaken Treg cell activity, promoting immune responses. This hypothesis has been partially tested using anti-IL-2 or anti-IL-2R Abs with antitumor effects that cannot be exclusively attributed to lack of IL-2 signaling in vivo. In this work, we pursued an alternative strategy to block IL-2 signaling in vivo, taking advantage of the trimeric structure of the IL-2R. We designed an IL-2 mutant that conserves the capacity to bind to the αβ-chains of the IL-2R but not to the γ-chain, thus having a reduced signaling capacity. We show our IL-2 mutein inhibits IL-2 Treg cell-dependent differentiation and expansion. Moreover, treatment with IL-2 mutein reduces Treg cell numbers and impairs tumor growth in mice. A mathematical mod...
γc-Signaling Cytokines Induce a Regulatory T Cell Phenotype in Malignant CD4+ T Lymphocytes
The Journal of Immunology, 2008
In this study, we demonstrate that malignant mature CD4+ T lymphocytes derived from cutaneous T cell lymphomas (CTCL) variably display some aspects of the T regulatory phenotype. Whereas seven cell lines representing a spectrum of primary cutaneous T cell lymphoproliferative disorders expressed CD25 and TGF-β, the expression of FOXP3 and, to a lesser degree, IL-10 was restricted to two CTCL cell lines that are dependent on exogeneous IL-2. IL-2, IL-15, and IL-21, all of which signals through receptors containing the common γ chain, induced expression of IL-10 in the IL-2-dependent cell lines as well as primary leukemic CTCL cells. However, only IL-2 and IL-15, but not IL-21, induced expression of FOXP3. The IL-2-triggered induction of IL-10 and FOXP3 expression occurred by signaling through STAT3 and STAT5, respectively. Immunohistochemical analysis of the CTCL tissues revealed that FOXP3-expressing cells were common among the CD7-negative enlarged atypical and small lymphocytes at ...
Immuno-oncology: Is it a new hope for cancer patients?
Cancer is the one of the leading causes of death, whose incidences is increasing day by day due to lack of understanding about its complete mechanism. Therefore, to understand complete mechanism of cancer, researchers started to move their focus from the cancer cell to the host and the environment in which the cancer grows, a very important component of which is the immune system. 1,2 The immune system comprises of innate and adaptive system which provides protection to the body against pathogens. The immune cell receptors recognize the foreign and activate the complex immune response signaling pathways which results in the elimination of pathogens. 3,4 The first problem with cancer cells is that they arise from our own cells, so some times unable to recognize as non self. Further, if they recognized, alters the immune response signaling pathways at various steps which results in failure of immune response. The cancer cells can avoid recognition and elimination by altering the immune response signaling pathways at various steps such as disrupting antigen recognition and presentation mechanisms, down regulates the MHC class I molecules or inhibiting the antigen processing mechanisms. Additionally, cancer cells may disrupt the pathways which are involved in controlling T-cell inhibition and activation, or by recruiting regulatory T cells (Treg) and Myeloid-derived suppressor cells (MDSC) which are immunosuppressive. Further, cancer cells may release of some of immunosuppressive immune factors such as adenosine and prostaglandin E2, and the enzyme Indoleamine 2,3-dioxygenase (IDO) which leads to progression of cancer. Immuno-oncology is the new and emerging field of cancer research that works to understand the interaction of the immune system with cancers cells and finds ways for harness of the patient's immune system to treat or prevent cancer. It targets only the immune system, not the cancer cells. 8 Researchers have been tried to understand this complex interaction for over a century, with tantalizing but unsustainable results. Recent advances in our understanding of antigen recognition, presentation and the molecules involved in T and B cell activation have provided new and excited immunotherapeutic strategies which can be used against the cancer cells. Some success in animal models has been observed and some molecules are now being under clinical trials. The interaction between our immune system and cancer is very complex process. Current strategies are based on agents that can break immune tolerance. 9
c-Signaling Cytokines Induce a Regulatory T Cell Phenotype in Malignant CD4+ T Lymphocytes
The Journal of Immunology, 2008
In this study, we demonstrate that malignant mature CD4 ؉ T lymphocytes derived from cutaneous T cell lymphomas (CTCL) variably display some aspects of the T regulatory phenotype. Whereas seven cell lines representing a spectrum of primary cutaneous T cell lymphoproliferative disorders expressed CD25 and TGF-, the expression of FOXP3 and, to a lesser degree, IL-10 was restricted to two CTCL cell lines that are dependent on exogeneous IL-2. IL-2, IL-15, and IL-21, all of which signals through receptors containing the common ␥ chain, induced expression of IL-10 in the IL-2-dependent cell lines as well as primary leukemic CTCL cells. However, only IL-2 and IL-15, but not IL-21, induced expression of FOXP3. The IL-2-triggered induction of IL-10 and FOXP3 expression occurred by signaling through STAT3 and STAT5, respectively. Immunohistochemical analysis of the CTCL tissues revealed that FOXP3-expressing cells were common among the CD7-negative enlarged atypical and small lymphocytes at the early skin patch and plaque stages. Their frequency was profoundly diminished at the tumor stage and in the CTCL lymph node lesions with or without large cell transformation. These results indicate that the T regulatory cell features are induced in CTCL T cells by common ␥ chain signaling cytokines such as IL-2 and do not represent a fully predetermined, constitutive phenotype independent of the local environmental stimuli to which these malignant mature CD4 ؉ T cells become exposed.