CiteULike: AlfonsoVicenteSuarez's tumor-rejection

Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines

Michael Morse — 2008-07-25T17:09:27-00:00

Blood, Vol. 112, No. 3. (1 August 2008), pp. 610-618.

CD4+CD25highFoxP3+ regulatory T (Treg) cells limit antigen-specific immune responses and are a cause of suppressed anticancer immunity. In preclinical and clinical studies, we assessed the immune consequences of FoxP3+ Treg-cell depletion in patients with advanced malignancies. We demonstrated that a CD25high targeting immunotoxin (denileukin diftitox) depleted FoxP3+ Treg cells, decreased Treg-cell function, and enhanced antigen-specific T-cell responses in vitro. We then attempted to enhance antitumor immune responses in patients with carcinoembryonic antigen (CEA)-expressing malignancies by Treg-cell depletion. In a pilot study (n = 15), denileukin diftitox, given as a single dose or repeated dosing, was followed by immunizations with dendritic cells modified with the fowlpox vector rF-CEA(6D)-TRICOM. By flow cytometric analysis, we report the first direct evidence that circulating CD4+CD25highFoxP3+ Treg cells are depleted after multiple doses of denileukin diftitox. Earlier induction of, and overall greater exposure to, the T-cell response to CEA was observed in the multiple-dose group, but not the single-dose group. These results indicate the potential for combining Treg-cell depletion with anticancer vaccines to enhance tumor antigen-specific immune responses and the need to explore dose and schedule of Treg depletion strategies in optimiz-ing vaccine efforts. This trial was registered at www.clinicaltrials.gov as no. NCT00128622 . 10.1182/blood-2008-01-135319

Tumor therapy in mice via antigen targeting to a novel, DC-restricted C-type lectin.

David Sancho — 2008-06-20T18:45:38-00:00

The Journal of clinical investigation, Vol. 118, No. 6. (2 June 2008), pp. 2098-2110.

The mouse CD8alpha(+) DC subset excels at cross-presentation of antigen, which can elicit robust CTL responses. A receptor allowing specific antigen targeting to this subset and its equivalent in humans would therefore be useful for the induction of antitumor CTLs. Here, we have characterized a C-type lectin of the NK cell receptor group that we named DC, NK lectin group receptor-1 (DNGR-1). DNGR-1 was found to be expressed in mice at high levels by CD8(+) DCs and at low levels by plasmacytoid DCs but not by other hematopoietic cells. Human DNGR-1 was also restricted in expression to a small subset of blood DCs that bear similarities to mouse CD8alpha(+) DCs. The selective expression pattern and observed endocytic activity of DNGR-1 suggested that it could be used for antigen targeting to DCs. Consistent with this notion, antigen epitopes covalently coupled to an antibody specific for mouse DNGR-1 were selectively cross-presented by CD8alpha(+) DCs in vivo and, when given with adjuvants, induced potent CTL responses. When the antigens corresponded to tumor-expressed peptides, treatment with the antibody conjugate and adjuvant could prevent development or mediate eradication of B16 melanoma lung pseudometastases. We conclude that DNGR-1 is a novel, highly specific marker of mouse and human DC subsets that can be exploited for CTL cross-priming and tumor therapy.

Tumor Growth Enhances Cross-Presentation Leading to Limited T Cell Activation without Tolerance

Linh Nguyen — 2008-06-20T17:43:30-00:00

J. Exp. Med., Vol. 195, No. 4. (11 February 2002), pp. 423-435.

Using a tumor model of spontaneously arising insulinomas expressing a defined tumor-associated antigen, we investigated whether tumor growth promotes cross-presentation and tolerance of tumor-specific T cells. We found that an advanced tumor burden enhanced cross-presentation of tumor-associated antigens to high avidity tumor-specific T cells, inducing T cell proliferation and limited effector function in vivo. However, contrary to other models, tumor-specific T cells were not tolerized despite a high tumor burden. In fact, in tumor-bearing mice, persistence and responsiveness of adoptively transferred tumor-specific T cells were enhanced. Accordingly, a potent T cell-mediated antitumor response could be elicited by intravenous administration of tumor-derived peptide and agonistic anti-CD40 antibody or viral immunization and reimmunization. Thus, in this model, tumor growth promotes activation of high avidity tumor-specific T cells instead of tolerance. Therefore, the host remains responsive to T cell immunotherapy. 10.1084/jem.20010032

The Immunodominant Antigen of an Ultraviolet-induced Regressor Tumor Is Generated by a Somatic Point Mutation in the DEAD Box Helicase p68

Purnima Dubey — 2007-11-12T20:25:31-00:00

J. Exp. Med., Vol. 185, No. 4. (17 February 1997), pp. 695-706.

The genetic origins of CD8+ T cell-recognized unique antigens to which mice respond when immunized with syngeneic tumor cells are unknown. The ultraviolet light-induced murine tumor 8101 expresses an H-2Kb-restricted immunodominant antigen, A, that induces cytolytic CD8+ T cells in vivo A+ 8101 cells are rejected by naive mice while A[-] 8101 tumor cells grow. To identify the antigen H-2Kb molecules were immunoprecipitated from A+ 8101 cells and peptides were eluted by acid. The sensitizing peptide was isolated by sequential reverse-phase HPLC and sequenced using microcapillary HPLC-triple quadruple mass spectrometry. The peptide, SNFVFAGI, matched the sequence of the DEAD box protein p68 RNA helicase except for a single amino acid substitution, caused by a single nucleotide change. This mutation was somatic since fibroblasts from the mouse of tumor origin expressed the wild-type sequence. The amino acid substitution created an anchor for binding of the mutant peptide to H-2Kb. Our results are consistent with mutant p68 being responsible for rejection of the tumor. Several functions of p68, which include nucleolar assembly and inhibition of DNA unwinding, may be mediated through its IQ domain, which was altered by the mutation. This is the first description of a somatic tumor-specific mutation in the coding region of a nucleic acid helicase. 10.1084/jem.185.4.695

Heterogeneity of tumorigenicity phenotype in murine tumors. I. Characterization of regressor and progressor clones isolated from a nonmutagenized ultraviolet regressor tumor

M Schmitt — 2007-11-12T20:24:27-00:00

J. Exp. Med., Vol. 153, No. 5. (1 May 1981), pp. 1344-1359.

We have shown that both regressor and progressor clones can be isolated from a UV regressor tumor, RD-1024. Although the daughter clones are characterized by differences in tumorigenic potential in normal transplant hosts, they nevertheless seem to express the same major tumor rejection antigens, because immunization with either the regressor parent tumor, RD-1024, or with regressor Cl 8 protects against subsequent challenge with progressor C1 4 or Cl 9. Consistent with the in vivo-generated data is the evidence that draining lymph node cells with functional specificity for regressor Cl 8 are capable of cross-reactive cytotoxicity in an in vitro chromium release assay.We have demonstrated an indirect interaction occurring in vivo between regressor and progressor cells, in that Cl 8 cells have the ability to influence the outcome of simultaneous or sequential challenge with Cl 4 or Cl 9 cells. Because 500 rad of gamma irradiation has been shown to compromise the ability of mice to respond to a primary challenge with tumor, an immunological mechanism is implicated in the ultimate rejection of progressor tumor in a doubly challenged host.The importance of these results lies in the knowledge that these interacting subpopulations have been isolated directly from a tumor growing in vivo and that no selection pressure has been exerted on the cells greater than the short in vitro culture period necessary for the isolation and expansion of individual clones. The apparent immunoregulatory potential in a tumor-bearing animal is thus seen to be modified in accordance with the phenotypic heterogeneity of the cells within that tumor. 10.1084/jem.153.5.1344

Comparative Analysis of Regulatory and Effector T Cells in Progressively Growing versus Rejecting Tumors of Similar Origins

Jack Bui — 2007-11-12T16:10:28-00:00

Cancer Res, Vol. 66, No. 14. (15 July 2006), pp. 7301-7309.

Although regulatory T cells (Tregs) have been detected in clinically apparent and experimentally induced tumors, the significance of their presence is obscured because past studies examined late-stage tumors that had formed in immunocompetent hosts and thus had evolved mechanisms to escape immunologic recognition and/or elimination. Herein, we report the first comparative analysis of the antitumor response to 3'-methylcholanthrene-induced tumors, which either grow progressively (progressor tumors) or are rejected by the immune system (regressor tumors). Surprisingly, we found that both progressor and regressor tumors harbored proliferating (i.e., activated) Foxp3+CD25+Tregs. However, progressor tumors contained a higher percentage of Tregs in the lymphocyte subset versus regressor tumors. The Tregs in progressor tumors were derived from peripheral CD25+ natural Tregs, accumulated early after tumor challenge and were actively proliferating, suggesting that progressor tumors recruited and/or activated endogenous Tregs as a mechanism of escaping immune destruction. To explore whether Tregs directly contributed to the progressive growth phenotype of progressor tumors, we monitored tumor outgrowth in naive wild-type recipients pretreated with either a control monoclonal antibody (mAb) or a depleting CD25-specific mAb. In mice predepleted of CD25+ cells, the tumors that subsequently developed displayed an increased accumulation of proliferating CD8+ T cells and were rejected. These results show that, although Tregs are activated in both regressor and progressor tumors, the ratio of regulatory to effector T cells is critical in determining whether the host successfully rejects the tumor or eventually succumbs to tumor outgrowth. (Cancer Res 2006; 66(14): 7301-9) 10.1158/0008-5472.CAN-06-0556

Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells -- Loeser et al. 204 (4): 879 -- The Journal of Experimental Medicine

2007-11-09T22:51:37-00:00

Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells -- Loeser et al. 204 (4): 879 -- The Journal of Experimental Medicine

2007-11-09T22:50:13-00:00