Lymphocytic infiltration in long-survival glioblastomas: Possible host's resistance

Lorenzo, N. Alcorta; Palma, Lucio; Stahmann, Nicole

doi:10.1007/bf01405238

Cited by 39 publications

(8 citation statements)

References 23 publications

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“…This discovery is complemented by earlier morphology-based analyses of T-cell-containing cuffs in GBM tissues. These cuffs were predominantly found in long-term surviving GBM patients (41) and were associated with an improved patient outcome (24,42). Further support comes from a very recent publication describing higher numbers of infiltrating CD8…”

Section: Discussionmentioning

confidence: 99%

Effector T-Cell Infiltration Positively Impacts Survival of Glioblastoma Patients and Is Impaired by Tumor-Derived TGF-β

Lohr

Ratliff

Huppertz

et al. 2011

Clinical Cancer Research

294

251

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Purpose: In glioma-in contrast to various other cancers-the impact of T-lymphocytes on clinical outcome is not clear. We investigated the clinical relevance and regulation of T-cell infiltration in glioma.Experimental Design: T-cell subpopulations from entire sections of 93 WHO II-IV gliomas were computationally identified using markers CD3, CD8, and Foxp3; survival analysis was then done on primary glioblastomas (pGBM). Endothelial cells expressing cellular adhesion molecules (CAM) were similarly computationally quantified from the same glioma tissues. Influence of prominent cytokines (as measured by ELISA from 53 WHO II-IV glioma lysates) on CAM-expression in GBM-isolated endothelial cells was determined using flow cytometry. The functional relevance of the cytokine-mediated CAM regulation was tested in a transmigration assay using GBM-derived endothelial cells and autologous T-cells.Results: Infiltration of all T-cell subsets increased in high-grade tumors. Most strikingly, within pGBM, elevated numbers of intratumoral effector T cells (T eff , cytotoxic and helper) significantly correlated with a better survival; regulatory T cells were infrequently present and not associated with GBM patient outcome. Interestingly, increased infiltration of T eff cells was related to the expression of ICAM-1 on the vessel surface. Transmigration of autologous T cells in vitro was markedly reduced in the presence of CAM-blocking antibodies. We found that TGF-b molecules impeded transmigration and downregulated CAM-expression on GBM-isolated endothelial cells; blocking TGF-b receptor signaling increased transmigration.Conclusions: This study provides comprehensive and novel insights into occurrence and regulation of T-cell infiltration in glioma. Specifically, targeting TGF-b1 and TGF-b2 might improve intratumoral T-cell infiltration and thus enhance effectiveness of immunotherapeutic approaches. Clin Cancer Res; 17(13); 4296-308. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Effector T-Cell Infiltration Positively Impacts Survival of Glioblastoma Patients and Is Impaired by Tumor-Derived TGF-β

Lohr

Ratliff

Huppertz

et al. 2011

Clinical Cancer Research

294

251

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“…Even though patients with a malignant glioma typically have impaired cell-mediated immune functions, it has been reported in a number of retrospective histopathological studies that survival correlates with the degree of lymphocytic infiltration in the tumor [5][6][7]. These findings have spawned interest in the immunology of brain tumors and experimentation with immunotherapy as a fourth treatment modality.…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy for malignant glioma using human recombinant interleukin-2 and activated autologous lymphocytes

1990

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Over the past few years, we and a number of other groups have conducted laboratory experiments and clinical trials of human recombinant interleukin-2 (rIL-2) alone or in combination with autologous 'activated' lymphocytes expressing in vitro tumoricidal activity in order to define toxicity and indicate its potential efficacy in patients with high-grade glioma. Because high rIL-2 concentrations can be attained with considerably less toxicity than with a systemic approach, all of the clinical trials, to date, have chosen a direct route; injecting lymphokine and cells into tumor tissue, the cystic cavity remaining after tumor excision, and/or neural parenchyma surrounding the site of tumor excision. While the rIL-2 therapies, as they have been applied in animal glioma models and patients, are safe, cerebral edema around the site of treatment has been a consistent finding. We have also seen, however, that steroid medications used by patients to control their cerebral edema may depress the anti-tumor activity of rIL-2 by depressing the capacity of lymphocytes to develop normal LAK activity. Although none of the immunotherapies involving rIL-2 have produced cures, the fact that sustained clinical responses have been reported, suggests that such therapies may slow a recurrence of tumor at the site of treatment. Efforts to improve outcome from rIL-2--based immunotherapies for malignant glioma are continuing with manipulation of rIL-2 dosing and scheduling and also with combinations of rIL-2 and other recombinant cytokines.

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“…Increased infiltration of lymphocytes into gliomas has been associated with an improved prognosis in a number of reports, 9,20,45 although other studies have failed to confirm this finding. 10 Some of this discrepancy likely relates to failure to adequately identify the varying subpopulations of lymphocytes present within such tumors.…”

Section: Discussionmentioning

confidence: 99%

“…8,51 The role of these infiltrating immune cells is not clear, and both anti-tumor and pro-tumor effects have been suggested. Several early studies documented a better prognosis in patients with glial cell tumors and larger lymphocytic infiltrates, 9,20,45 although other studies failed to show such a benefit. 10 The heterogeneous nature of the infiltrating lymphocyte population may, in part, account for this discrepancy but was not examined in these reports.…”

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confidence: 99%

Characterization of Immune Cell Infiltration Into Canine Intracranial Meningiomas

et al. 2011

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Meningiomas are the most common intracranial tumors in dogs. A variety of inflammatory cells have been shown to invade these tumors in people, but little is known about interactions between the immune system and naturally occurring brain tumors in dogs. The purpose of this study was to investigate the presence of a variety of immune cell subsets within canine intracranial meningiomas. Twenty-three formalin-fixed, paraffin-embedded tumor samples were evaluated using immunohistochemistry with antibodies specific for CD3, CD79a, CD18, CD11d (aD), CD45RA, forkhead box P3, and Toll-like receptors 4 and 9. Immune cell infiltration was evident in all samples, with a predominance of CD3 þ T cells. Large numbers of CD18 þ microglia and macrophages were noted surrounding and infiltrating the tumors, and a subset of these cells within the tumor appeared to be CD11d

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Lymphocytic infiltration in long-survival glioblastomas: Possible host's resistance

Cited by 39 publications

References 23 publications

Effector T-Cell Infiltration Positively Impacts Survival of Glioblastoma Patients and Is Impaired by Tumor-Derived TGF-β

Effector T-Cell Infiltration Positively Impacts Survival of Glioblastoma Patients and Is Impaired by Tumor-Derived TGF-β

Immunotherapy for malignant glioma using human recombinant interleukin-2 and activated autologous lymphocytes

Characterization of Immune Cell Infiltration Into Canine Intracranial Meningiomas

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