Increased Immune Gene Expression and Immune Cell Infiltration in High-Grade Astrocytoma Distinguish Long-Term from Short-Term Survivors

Donson, Andrew M.; Birks, Diane K.; Schittone, Stephanie A.; Kleinschmidt‐DeMasters, Bette K.; Sun, Derrick; Hemenway, Molly; Handler, Michael H.; Waziri, Allen; Wang, Michael; Foreman, Nicholas K.

doi:10.4049/jimmunol.1103373

Cited by 66 publications

(84 citation statements)

References 39 publications

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“…Given limitations of tissue availability, we were unable to explore whether the LTS phenotype in our cohort is linked to recently characterized gene expression or DNA methylation signatures (29)(30)(31). The first high-throughput approaches have indeed suggested links between LTS and decreased retinoic acid signaling (32), enhanced immunerelated gene expression (33), or distinct DNA methylation profiles (34), but more studies with larger patient populations seem to be required to decide whether tumor rather than host factors are chiefly responsible for LTS. …”

Section: Discussionmentioning

confidence: 99%

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Hartmann¹,

Hentschel

Simon

et al. 2013

Clinical Cancer Research

165

108

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Purpose: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in World Health Organization (WHO) grades II and III gliomas, but rare in primary glioblastomas, and associated with longer survival.Experimental Design: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival >36 months (LTS-36), including 33 patients surviving >60 months (LTS-60), with 257 patients surviving <36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations, and IDH1/2 mutations were determined by standard techniques.Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23 of 67 patients) as opposed to 4.3% in controls (11 of 257 patients). Long-term survivors with IDH1/2-mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Long-term survivors with IDH1/2 wild-type showed no distinguishing features from other patients with IDH1/2 wild-type glioblastomas except for a higher rate of MGMT promoter methylation. Similarly, among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less-frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had less frequently TP53 mutations and radiotherapy alone as initial treatment.Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade II/III gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

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Section: Discussionmentioning

confidence: 99%

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Hartmann¹,

Hentschel

Simon

et al. 2013

Clinical Cancer Research

165

108

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“…Often revealed by hierarchical clustering techniques or outcome correlation studies, these signatures distinguish multiple different immune cell types [32][33][34][35][36][37] and recapitulate immunohistochemistry-based observations in breast cancer that link tumor-infiltrating immune cell abundance to disease-free survival and overall survival of patients [30,[36][37][38][39][40][41][42]. More recently, similar studies involving presurgical breast tumor biopsies have begun to demonstrate associations between immunity-related genes and tumor responsiveness to neoadjuvant chemotherapy [22,44,45,63,64].…”

Section: Discussionmentioning

confidence: 74%

“…In more recent years, microarray expression profiling studies in breast and other tumor types have identified immune gene signatures from whole tumor RNA extracts that reflect the abundance of tumor-infiltrating immune cells [30][31][32][33][34][35][36][37][38]. We and others have found that the biological and phenotypic properties of the genes comprising these signatures implicate distinct immune cell lineages [34][35][36][37]39,40], and that combinations of these immune genes correlate with patient outcomes ranging from recurrence-free survival [30,32,[36][37][38][39][40][41][42][43] to tumor regression in the neoadjuvant setting [44][45][46][47].…”

Section: Introductionmentioning

confidence: 99%

Dual roles for immune metagenes in breast cancer prognosis and therapy prediction

et al. 2014

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Background: Neoadjuvant chemotherapy for breast cancer leads to considerable variability in clinical responses, with only 10 to 20% of cases achieving complete pathologic responses (pCR). Biological and clinical factors that determine the extent of pCR are incompletely understood. Mounting evidence indicates that the patient's immune system contributes to tumor regression and can be modulated by therapies. The cell types most frequently observed with this association are effector tumor infiltrating lymphocytes (TILs), such as cytotoxic T cells, natural killer cells and B cells. We and others have shown that the relative abundance of TILs in breast cancer can be quantified by intratumoral transcript levels of coordinately expressed, immune cell-specific genes. Through expression microarray analysis, we recently discovered three immune gene signatures, or metagenes, that appear to reflect the relative abundance of distinct tumor-infiltrating leukocyte populations. The B/P (B cell/plasma cell), T/NK (T cell/natural killer cell) and M/D (monocyte/dendritic cell) immune metagenes were significantly associated with distant metastasis-free survival of patients with highly proliferative cancer of the basal-like, HER2-enriched and luminal B intrinsic subtypes. Methods: Given the histopathological evidence that TIL abundance is predictive of neoadjuvant treatment efficacy, we evaluated the therapy-predictive potential of the prognostic immune metagenes. We hypothesized that pre-chemotherapy immune gene signatures would be significantly predictive of tumor response. In a multi-institutional, meta-cohort analysis of 701 breast cancer patients receiving neoadjuvant chemotherapy, gene expression profiles of tumor biopsies were investigated by logistic regression to determine the existence of therapy-predictive interactions between the immune metagenes, tumor proliferative capacity, and intrinsic subtypes. Results: By univariate analysis, the B/P, T/NK and M/D metagenes were all significantly and positively associated with favorable pathologic responses. In multivariate analyses, proliferative capacity and intrinsic subtype altered the significance of the immune metagenes in different ways, with the M/D and B/P metagenes achieving the greatest overall significance after adjustment for other variables. Conclusions: Gene expression signatures of infiltrating immune cells carry both prognostic and therapy-predictive value that is impacted by tumor proliferative capacity and intrinsic subtype. Anti-tumor functions of plasma B cells and myeloid-derived antigen-presenting cells may explain more variability in pathologic response to neoadjuvant chemotherapy than previously recognized.

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“…Standard error is represented by error bars Jacobs suggested a moderate increase in survival of GBM patients displaying less Treg infiltration, compared to patients with a high proportion of intratumoral Treg [14]. Efforts to improve immunotherapy, supported by the work of Donson 2012, confirm the importance of the expression of local immune-related genes on the survival of patients with high-grade glioma [23].…”

Section: Discussionmentioning

confidence: 90%

Circulating T regulatory cells migration and phenotype in glioblastoma patients: an in vitro study

Vasco¹,

Canazza²,

Rizzo³

et al. 2013

J Neurooncol

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Glioblastoma multiforme (GBM) is the most aggressive primary human brain tumor. The relatively high amount of T regulatory lymphocytes present in the tumor, contributes to the establishment of an immunosuppressive microenvironment. Samples of peripheral blood were collected from GBM patients and healthy controls and a purified population of Treg (CD4 ? /CD25 bright ) was isolated using flow cytometric cell sorting. Treg migrating capacities toward human glioma cell line conditioned medium were evaluated through an in vitro migration test. Our data show that supernatants collected from GBM cell lines were more attractant to Treg when compared to complete standard medium. The addition of an anti-CCL2 antibody to conditioned medium decreased conditioned mediumdepending Treg migration, suggesting that CCL2 (also known as Monocyte Chemoattractant Protein, MCP-1) is implicated in the process. The number of circulating CD4? /lL or Treg/lL was similar in GBM patients and controls. Specific Treg markers (FOXP3; CD127; Helios; GITR; CTLA4; CD95; CCR2, CCR4; CCR7) were screened in peripheral blood and no differences could be detected between the two populations. These data confirm that the tumor microenvironment is attractive to Treg, which tend to migrate toward the tumor region changing the immunological response. Though we provide evidence that CCL2 is implicated in Treg migration, other factors are needed as well to provide such effect.

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Increased Immune Gene Expression and Immune Cell Infiltration in High-Grade Astrocytoma Distinguish Long-Term from Short-Term Survivors

Cited by 66 publications

References 39 publications

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Long-Term Survival in Primary Glioblastoma With Versus Without Isocitrate Dehydrogenase Mutations

Dual roles for immune metagenes in breast cancer prognosis and therapy prediction

Circulating T regulatory cells migration and phenotype in glioblastoma patients: an in vitro study

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