CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative (original) (raw)
Related papers
The Journal of Immunology, 2007
Aiming to get a better insight on the impact of regulatory CD25 ؉ CD4 ؉ T cells in tumor-immunobiology, a simple mathematical model was previously formulated and studied. This model predicts the existence of two alternative modes of uncontrolled tumor growth, which differ on their coupling with the immune system, providing a plausible explanation to the observation that the development of some tumors expand regulatory T cells whereas others do not. We report now the study of how these two tumor classes respond to different therapies, namely vaccination, immune suppression, surgery, and their different combinations. We show 1) how the timing and the dose applied in each particular treatment determine whether the tumor will be rejected, with or without concomitant autoimmunity, or whether it will continue progressing with slower or faster pace; 2) that both regulatory T cell-dependent and independent tumors are equally sensitive to vaccination, although the former are more sensitive to T cell depletion treatments and are unresponsive to partial surgery alone; 3) that surgery, suppression, and vaccination treatments, can synergistically improve their individual effects, when properly combined. Particularly, we predict rational combinations helping to overcome the limitation of these individual treatments on the late stage of tumor development.
European Journal of Immunology, 2002
Although it is known that the immune system can mount responses to a variety of tumors it is clear that most tumors exhibit weak or even undetectable immunogenicity. Recent findings suggest that the lack of tumor immunogenicity is partly due to a population of cells called CD4 + CD25 + regulatory T cells since depletion of these cells in mice can result in tumor rejection. These cells have also been shown to inhibit the development of organ-specific autoimmune diseases suggesting that they inhibit immune responses to tissue-specific selfantigens. Such immune responses may also mediate tumor rejection. Alternatively, immune responses in mice depleted of regulatory cells may target tumor antigens that are not tissuespecific, but which are shared by tumors of diverse origins. In experiments performed to discriminate between these possibilities we found, using the murine colorectal tumor CT26, that tumor immunity stimulated in the absence of regulatory cells is not restricted to tumors of colorectal origin, but is effective against tumors of different histological types such as B cell lymphomas and a renal cell carcinoma. By comparing this to CT26-induced immunity through the use of adjuvant we show that the generation of cross-reactive tumor immunity is a specific manifestation of CD25 + regulatory cell depletion. The generation of CD4 + T cells capable of mediating tumor rejection is another important feature of tumor immunity induced in the absence of CD25 + cells.
Journal of Theoretical Biology, 2007
Aiming to get a better insight on the impact of regulatory CD25 ؉ CD4 ؉ T cells in tumor-immunobiology, a simple mathematical model was previously formulated and studied. This model predicts the existence of two alternative modes of uncontrolled tumor growth, which differ on their coupling with the immune system, providing a plausible explanation to the observation that the development of some tumors expand regulatory T cells whereas others do not. We report now the study of how these two tumor classes respond to different therapies, namely vaccination, immune suppression, surgery, and their different combinations. We show 1) how the timing and the dose applied in each particular treatment determine whether the tumor will be rejected, with or without concomitant autoimmunity, or whether it will continue progressing with slower or faster pace; 2) that both regulatory T cell-dependent and independent tumors are equally sensitive to vaccination, although the former are more sensitive to T cell depletion treatments and are unresponsive to partial surgery alone; 3) that surgery, suppression, and vaccination treatments, can synergistically improve their individual effects, when properly combined. Particularly, we predict rational combinations helping to overcome the limitation of these individual treatments on the late stage of tumor development. The Journal of Immunology, 2007, 179: 5659 -5668.
PLoS ONE, 2012
Background: The regulatory T cells (Tregs) can actively suppress the immune responses. However, literature about detailed changes of host effective and suppressive immunities before and after depletion of Tregs in ovarian carcinomas, is rare. Materials and Methods: Ovarian cancer patients and the ascitogenic animal model were employed. Immunologic profiles with flow cytometric analyses, immunohistochemistric staining, RT-PCR, ELISA, and ELISPOT assays were performed. In vivo depletion of Treg cells with the mAb PC61was also performed in the animal model. Results: The cytokines, including IL-4 (p = 0.017) and TNF-a (p = 0.046), significantly decreased while others such as TGF-b (p = 0.013), IL-6 (p = 0.016), and IL-10 (p = 0.018) were elevated in ascites of ovarian cancer patients, when the disease progressed to advanced stages. The ratio of CD8 + T cell/Treg cell in ascites was also lower in advanced diseases than in early diseases (advanced 7.3760.64 vs. early 14.2563.11, p = 0.037). The kinetic low-dose CD25 Ab depletion group had significantly lower intra-peritoneal tumor weight (0.2060.03 g) than the sequential high-dose (0.6960.06 g) and sequential low-dose (0.6760.07 g) CD25 Ab deletion groups (p = 0.001) after 49 days of tumor challenge in the animal. The kinetic lowdose CD25 Ab depletion group generated the highest number of IFN-c-secreting, mesothelin-specific T lymphocytes compared to the other groups (p,0.001). Conclusions: The imbalance between effective and suppressive immunities becomes more severe as a tumor progresses. The depletion of Treg cells can correct the imbalance of immunologic profiles and generate potent anti-tumor effects. Targeting Treg cells can be a new strategy for the immunotherapy of ovarian carcinoma.
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.
Immunoregulatory T cells in tumor immunity
Current Opinion in Immunology, 2004
One mechanism of cancer immune evasion is the suppression of anti-tumor immunity by immunoregulatory T cells. Recent studies of these cells, especially CD4 þ CD25 þ T cells and NKT cells, have revealed molecular and cellular mechanisms of immunosuppression. Mouse studies have shown that either removing immunoregulatory T cells or blocking an immunoregulatory pathway induced by such cells unmasks natural tumor immunosurveillance and improves responses to cancer vaccines. Studies of the corresponding T-cell populations in human cancer patients support a similar role for immunoregulatory T cells in immunosuppression, implying that blocking immunoregulatory T-cell activity might improve the efficacy of tumor vaccines or the immunotherapy of cancer.
Journal of Clinical Investigation, 1998
Cyclophosphamide (CTX) increases the antitumor effectiveness of adoptive immunotherapy in mice, and combined immunotherapy regimens are now used in some clinical trials. However, the mechanisms underlying the synergistic antitumor responses are still unclear. The purpose of this study was (a) to evaluate the antitumor response to CTX and adoptive immunotherapy in mice bearing four different syngeneic tumors (two responsive in vivo to CTX and two resistant); and (b) to define the mechanism(s) of the CTX-immunotherapy synergism. Tumor-bearing DBA/2 mice were treated with a single injection of CTX followed by an intravenous infusion of tumor-immune spleen cells. In all the four tumor models, a single CTX injection resulted in an impressive antitumor response to the subsequent injection of spleen cells from mice immunized with homologous tumor cells independently of the in vivo response to CTX alone. Detailed analysis of the antitumor mechanisms in mice transplanted with metastatic Friend leukemia cells revealed that (a) the effectiveness of this combined therapy was dependent neither on the CTX-induced reduction of tumor burden nor on CTX-induced inhibition of some putative tumor-induced suppressor cells; (b) the CTX/immune cells' regimen strongly protected the mice from subsequent injection of FLC, provided the animals were also preinoculated with inactivated homologous tumor together with the immune spleen cells; (c) CD4(+) T immune lymphocytes were the major cell type responsible for the antitumor activity; (d) the combined therapy was ineffective in mice treated with antiasialo-GM1 or anti-IFN-alpha/beta antibodies; (e) spleen and/ or bone marrow cells from CTX-treated mice produced soluble factors that assisted in proliferation of the spleen cells. Altogether, these results indicate that CTX acts via bystander effects, possibly through production of T cell growth factors occurring during the rebound events after drug administration, which may sustain the proliferation, survival, and activity of the transferred immune T lymphocytes. Thus, our findings indicate the need for reappraisal of the mechanisms underlying the synergistic effects of CTX and adoptive immunotherapy, and may provide new insights into the definition of new and more effective strategies with chemotherapy and adoptive immunotherapy for cancer patients.
Do CD4+CD25+ Immunoregulatory T Cells Hinder Tumor Immunotherapy?
Journal of Immunotherapy, 2002
After years of banishment from mainstream immunology, the notion that one subset of T cells can exert regulatory effects on other T lymphocytes is back in fashion. Recent work in knockout and transgenic mice has begun to bring molecular definition to our understanding of immunoregulatory CD4 + CD25 + T cells (Treg/Th3/Tr1). The identification of the glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR, also known as TNFRSF18) expressed on T regulatory cells might afford new therapeutic opportunities. Another possible therapeutic intervention could be the blockade of signaling through the molecular pair of tumor necrosis factor-related activation induced cytokine (TRANCE) and receptor activator of NF-[kappa]B (RANK). Based on the available evidence from experimental mouse tumor models, however, it seems that simply blocking or even eliminating T regulatory function will not be enough to manage established tumors. The challenge for immunotherapists now is to overcome immunosuppression using the knowledge gained through the understanding of T regulatory cell function.