Immune cell infiltrate differences in pilocytic astrocytoma and glioblastoma: evidence of distinct immunological microenvironments that reflect tumor biology

Laboratory investigation

Full access

Object

The tumor microenvironment in astrocytomas is composed of a variety of cell types, including infiltrative inflammatory cells that are dynamic in nature, potentially reflecting tumor biology. In this paper the authors demonstrate that characterization of the intratumoral inflammatory infiltrate can distinguish high-grade glioblastoma from low-grade pilocytic astrocytoma.

Methods

Tumor specimens from ninety-one patients with either glioblastoma or pilocytic astrocytoma were analyzed at the University of California, San Francisco. A systematic neuropathology analysis was performed. All tissue was collected at the time of the initial surgery prior to adjuvant treatment. Immune cell infiltrate not associated with necrosis or hemorrhage was analyzed on serial 4-μm sections. Analysis was performed for 10 consecutive hpfs and in 3 separate regions (total 30 × 0.237 mm2). Using immunohistochemistry for markers of infiltrating cytotoxic T cells (CD8), natural killer cells (CD56), and macrophages (CD68), the inflammatory infiltrates in these tumors were graded quantitatively and classified based on microanatomical location (perivascular vs intratumoral). Control markers included CD3, CD20, and human leukocyte antigen.

Results

Glioblastomas exhibited significantly higher perivascular (CD8) T-cell infiltration than pilocytic astrocytomas (62% vs 29%, p = 0.0005). Perivascular (49%) and intratumoral (89%; p = 0.004) CD56-positive cells were more commonly associated with glioblastoma. The CD68-positive cells also were more prevalent in the perivascular and intratumoral space in glioblastoma. In the intratumoral space, all glioblastomas exhibited CD68-positive cells compared with 86% of pilocytic astrocytomas (p = 0.0014). Perivascularly, CD68-positive infiltrate was also more prevalent in glioblastoma when compared with pilocytic astrocytoma (97% vs 86%, respectively; p = 0.0003). The CD3-positive, CD20-positive, and human leukocyte antigen-positive infiltrates did not differ between glioblastoma and pilocytic astrocytoma.

Conclusions

This analysis suggests a significantly distinct immune profile in the microenvironment of high-grade glioblastoma versus low-grade pilocytic astrocytoma. This difference in tumor microenvironment may reflect an important difference in the tumor biology of glioblastoma.

Abbreviation used in this paper: HLA = human leukocyte antigen.

Abstract

Object

The tumor microenvironment in astrocytomas is composed of a variety of cell types, including infiltrative inflammatory cells that are dynamic in nature, potentially reflecting tumor biology. In this paper the authors demonstrate that characterization of the intratumoral inflammatory infiltrate can distinguish high-grade glioblastoma from low-grade pilocytic astrocytoma.

Methods

Tumor specimens from ninety-one patients with either glioblastoma or pilocytic astrocytoma were analyzed at the University of California, San Francisco. A systematic neuropathology analysis was performed. All tissue was collected at the time of the initial surgery prior to adjuvant treatment. Immune cell infiltrate not associated with necrosis or hemorrhage was analyzed on serial 4-μm sections. Analysis was performed for 10 consecutive hpfs and in 3 separate regions (total 30 × 0.237 mm2). Using immunohistochemistry for markers of infiltrating cytotoxic T cells (CD8), natural killer cells (CD56), and macrophages (CD68), the inflammatory infiltrates in these tumors were graded quantitatively and classified based on microanatomical location (perivascular vs intratumoral). Control markers included CD3, CD20, and human leukocyte antigen.

Results

Glioblastomas exhibited significantly higher perivascular (CD8) T-cell infiltration than pilocytic astrocytomas (62% vs 29%, p = 0.0005). Perivascular (49%) and intratumoral (89%; p = 0.004) CD56-positive cells were more commonly associated with glioblastoma. The CD68-positive cells also were more prevalent in the perivascular and intratumoral space in glioblastoma. In the intratumoral space, all glioblastomas exhibited CD68-positive cells compared with 86% of pilocytic astrocytomas (p = 0.0014). Perivascularly, CD68-positive infiltrate was also more prevalent in glioblastoma when compared with pilocytic astrocytoma (97% vs 86%, respectively; p = 0.0003). The CD3-positive, CD20-positive, and human leukocyte antigen-positive infiltrates did not differ between glioblastoma and pilocytic astrocytoma.

Conclusions

This analysis suggests a significantly distinct immune profile in the microenvironment of high-grade glioblastoma versus low-grade pilocytic astrocytoma. This difference in tumor microenvironment may reflect an important difference in the tumor biology of glioblastoma.

Alterations in immune system function may represent a critical step for glioma pathogenesis. Biological or therapeutic events that modulate the intracranial glial immunological microenvironment may have significant consequences in affecting the tumor microenvironment. Supporting this contention is the observation that a serious allergy history has been associated with a lower individual lifetime risk for developing a high-grade glioma,2,34 suggesting that a chronically overactive immune system may be protective. In addition, HIV-mediated or post–organ transplant iatrogenic immunosuppression may increase the risk for glioblastoma, further demonstrating the potential need for a relative immunosuppression step in glioma pathogenesis.8,11,20,22,29 The standardized histopathology grading of gliomas provides a model to test whether high-grade gliomas affect the surrounding immunological microenvironment in a manner distinct from low-grade pilocytic astrocytoma.

Markers of infiltrating cytotoxic T cells (CD8), natural killer cells (CD56), and macrophages (CD68) in glioma tissue may be associated with specific glioma pathogenesis and may be distinct in high-grade and low-grade gliomas.3 Furthermore, the extent and location of the immune cells may influence tumor-host interaction and may be related to tumor growth. For instance, perivascular inflammatory infiltrates may differ from intratumoral cytotoxic T-cell infiltrates due to differences in the proximity of the latter to the tumor cell.12,35 The latter may be associated with a more direct functional effect on tumor cells. However, a detailed characterization of inflammatory infiltrates with respect to their localization and correlation of these infiltrates with the biological nature of glioblastoma and pilocytic astrocytomas is currently not available.

We hypothesized that by determining the extent and type of inflammatory infiltrates in perivascular and intratumoral spaces, we could potentially identify differences in these patterns that could distinguish between different tumor grades, more specifically whether a predominantly noninfiltrative low-grade pilocytic astrocytoma and a highly infiltrative high-grade glioblastoma demonstrated different immune cell profiles. In this study, we present an analysis evaluating CD8-positive T-cell, CD56, and CD68 immune cell infiltrates in both the perivascular and intratumoral regions of tumors obtained from 91 patients with either pilocytic astrocytoma or glioblastoma.

Methods

Patient Population

This study was drawn from 91 patients who were diagnosed with gliomas at our institution between 1995 and 2010. Sixty-three of these patients had glioblastoma and 28 had pilocytic astrocytoma. The patients were selected after a central pathology review and after determination of the presence of sufficient tissue for analysis. All material was obtained from the initial surgery of patients prior to any adjuvant treatment. All study protocols were reviewed and approved by the Committee on Human Research at the University of California, San Francisco.

Histological Analysis and Immunohistochemistry

A systematic neuropathology review was performed based on the WHO classification.18 All slides were reviewed to determine histological features and each histological parameter was recorded. All glioblastomas had multiple mitoses, endothelial vascular proliferation, and foci of necrosis. All pilocytic astrocytomas had classical cytoarchitecture with biphasic pattern and Rosenthal fibers. Cases without sufficient tissue for evaluation were excluded. The overall degree of inflammatory infiltrates was evaluated using H & E stains, and the regions of tissue with the highest degree of inflammation (not associated with necrosis or hemorrhage) were selected for analysis. Immunohistochemical studies were performed on serial 4-μm sections using standard methodology (for source and dilutions, see below). Each staining batch included an external negative control without the primary antibody, a biological negative control of normal brain tissue, and a positive control (either from a lymph node or tonsil). Immunohistochemical analyses were performed on a semiquantitative basis using a subjective 4-tier approach. The scoring was performed in 10 consecutive hpfs and in 3 separate regions of the tissue (a total of 30 × 0.237 mm2). Inflammatory infiltrates within the tumor tissue (intratumoral) were evaluated separately from inflammatory cells within the Virchow-Robin spaces (perivascular).

Immunohistochemical staining was performed for CD3 (DAKO; dilution 1:400), CD8 (DAKO; dilution 1:320), CD 20 (DAKO; dilution 1:1200), CD56 (Zymed; Dilution 1:100), CD68 (DAKO KP1: dilution 1:4000), and HLA (Abcam; dilution 1:100) both perivascularly and intratumorally. The intratumoral infiltrate was scored 0–3 using the following scheme: 0 = rare infiltrate of less then 5 cells per 10 hpfs; 1 = focal infiltrate of between 5 and 20 cells per 10 hpfs; 2 = intermediate infiltrate of between 20 and 100 cells per 10 hpfs; and 3 = extensive infiltrate of greater than 100 cells per 10 hpfs. For perivascular T-cell infiltrate, the scoring system (again scored 0–3) was as follows: 0 = rare infiltrate of less than 1 cell per vessel; 1 = focal infiltrate of between 2 and 5 cells per vessel; 2 = intermediate infiltrate of between 5 and 20 cells per vessel; and 3 = extensive infiltrate of greater than 20 cells per vessels. For the perivascular staining score, at least 20 small vessels (arterioles/arteries) were identified for each 10 hpfs.

Statistical Analysis

The raw data were tabulated using Microsoft Excel (Microsoft Corp.). Bivariate comparisons of binary data, small sets of binary data, and continuous data were performed using the chi-square test, Fisher exact test, or t-test, respectively. For all statistical investigations, tests for significance were 2-sided, with a (2-tailed) probability value threshold of 0.05 considered statistically significant. Unless otherwise stated, all continuous values presented are mean ± SD.

Results

CD20-, HLA- and CD3-Positive Cells

We analyzed tissues for the presence of B cells and T cells to determine the overall features of the inflammatory infiltrates in glioblastoma (Fig. 1) and pilocytic astrocytoma (Fig. 2). There were essentially no CD20-positive cells within the tumor tissue of either glioblastoma or pilocytic astrocytoma and only 4 cases within the pilocytic astrocytoma group had focal perivascular B cells.

Fig. 1.
Fig. 1.

Summary data of semiquantitative analysis of immunohistochemistry for inflammatory markers in high-grade glioblastoma.

Fig. 2.
Fig. 2.

Summary data of semiquantitative analysis of immunohistochemistry for inflammatory markers in low-grade pilocytic astrocytoma.

The density and distribution of HLA-positive cells that represented all the nucleated inflammatory cells, including polymorphs, monocytes, lymphocytes, and eosinophils, were similar in both glioblastoma and pilocytic astrocytoma. The number of CD3-positive cells was similar between glioblastoma and pilocytic astrocytoma with slightly more CD3-positive cells in pilocytic astrocytoma in both the intratumoral and perivascular regions. Nevertheless, both tumor types had very few CD3-positive cells in either compartment. Only 3 glioblastomas demonstrated high numbers of CD3-positive cells, and in all 3 cases the infiltrates were increased both within the tumor and in perivascular spaces.

CD8-Positive T-Cell Infiltrates

Overall, significantly more glioblastomas had intermediate or extensive perivascular CD8-positive T cells than intratumoral CD8-positive T cells (73% vs 46%, respectively; p = 0.0018). Conversely, pilocytic astrocytomas had corresponding and similar numbers of CD8-positive T-cell infiltrates in the perivascular and intratumoral spaces. The extent of the CD8-positive T-cell infiltrate was similar in the intratumoral (75%) and perivascular (71%) compartment in pilocytic astrocytomas.

CD56-Positive and CD68-Positive Immune Cell infiltrate

CD56-positive cells, a common marker for natural killer cells, were more commonly observed in glioblastoma (Fig. 3), both in the perivascular (49%) and intratumoral (89%) compartments, than in pilocytic astrocytomas (p = 0.004). Pilocytic astrocytomas did not demonstrate significant CD56-positive monocyte infiltrate (Fig. 4) either perivascularly (4%) or intratumorally (0%). This difference in CD56-positive infiltrates suggests that natural killer cells may play an important role in the pathogenesis or tumor biology of glioblastoma.

Fig. 3.
Fig. 3.

Photomicrographs demonstrating the scoring classification for rare (A), intermediate (B), and extensive (C) inflammatory infiltrates for intratumoral CD68 in glioblastoma. Original magnification × 20.

Fig. 4.
Fig. 4.

Representative photomicrographs for various inflammatory cell markers as indicated in pilocytic astrocytoma. This is a representative staining of different antigens for the pilocytic astrocytoma group demonstrating the different markers of immune cell infiltrate that were analyzed in the low-grade pilocytic astrocytomas. Original magnification × 20.

CD68-positive cells, another marker for monocytes and macrophages,14 were also commonly observed in glioblastoma, both in the perivascular and intratumoral regions. In the intratumoral space, all glioblastomas exhibited CD68-positive macrophage infiltrate to a significantly greater degree than the intratumor CD68-positive infiltrate in pilocytic astrocytoma (86% of pilocytic astrocytomas exhibited CD68-positive infiltrate; p = 0.0014). The perivascular CD68-positive infiltrate was also more commonly observed in glioblastoma than in pilocytic astrocytoma (97% vs 86%, respectively; p = 0.0003; Fig. 5). The perivascular and intratumoral infiltrates of CD68-positive monocytes and macrophages were similar in high-grade glioblastoma.

Fig. 5.
Fig. 5.

Bar graph of CD8 and CD68 immunohistochemistry demonstrating the inflammatory infiltrate differences in intratumoral and perivascular immune cell infiltrate in glioblastoma.

Discussion

In major histocompatibility complex Class-I antigenexpressing tumors, tumor-associated antigens can be recognized by cytotoxic CD8-positive T cells.16,26,39 In the present study, we analyzed specific immune cell infiltrates such as CD8, CD56, and CD68 cells within the intratumoral and perivascular space of pilocytic astrocytoma and glioblastoma to demonstrate that infiltrative high-grade glioblastomas have a significantly different immunological profile than lower grade pilocytic astrocytomas. This report is one of the largest studies reported to date characterizing T-cell, natural killer cell, and macrophage density in different spatial tumor compartments of high-grade glioblastoma and low-grade pilocytic astrocytoma.

Infiltrating CD8-positive T cells have been characterized in melanoma,4,5,19 ovarian cancer,6,28,40 and colorectal cancer.10,21,23,24 However, currently the relationship between the clinical outcome of glioma patients and CD8-positive T-cell infiltrates is not fully characterized.7 Early studies with high-grade gliomas suggested that while there was an increased T-cell infiltrate in these tumors, the extent of T-cell infiltrates did not correlate with overall survival.27,32 These studies suggested that 28%–60% of high-grade gliomas have intratumoral T-cell infiltrates, but the spatial location of these cells with respect to tumor cells was not specifically analyzed in these studies.9,13,30,33

Our data confirm the presence of CD8-positive T-cell infiltrate in high-grade glioblastoma, but also demonstrate that the perivascular CD8-positive T-cell infiltrates in high-grade glioma are significantly higher than those in noninfiltrative low-grade pilocytic astrocytomas. Our data suggest that in glioblastomas, there are many more CD8-positive T cells within the Virchow-Robin perivascular spaces compared with the intratumoral compartment (73% vs 46%, respectively; p = 0.0018). In contrast, the extent of CD8-positive T-cell infiltrate was similar in both compartments in pilocytic astrocytoma. This difference suggests a distinct glioma microenvironment in the infiltrative high-grade glioblastoma that demonstrably influences the local immune environment. Our group as well as others have identified B7-H1 as a potential mechanism of survival of malignant gliomas, and perhaps such immune-inhibiting molecules may act to eliminate cytotoxic T cells that may provide a potential mechanism for our observations in this study.1,15,17,25,31,36–39 We are currently conducting additional studies to determine the causal association between the density of CD8-positive T cells and the expression of proteins associated with immune evasion in glioblastoma.

In our data, glioblastoma also demonstrated significantly more extensive CD56-positive and CD68-positive cell infiltrates in both the intratumoral and perivascular spaces compared with pilocytic astrocytoma. CD56-positive inflammatory natural killer cells were virtually absent in pilocytic astrocytoma, while CD68-positive macrophages were present at a significantly lower density than observed in our glioblastoma patients. CD56 markers are commonly used to identify natural killer cells, but some have suggested that monocytes may also express this immune marker.3 Taken together, these observations suggest that glioblastomas induce a unique and distinct natural killer cell and monocyte/macrophage response that exhibits a unique immunological profile. Our analysis characterizing different intratumoral and perivascular macrophage and natural killer cell densities between pilocytic astrocytoma and glioblastoma suggests a distinct immune cell response in noninfiltrative versus infiltrative tumors.

A limitation of this study is that these data represent a retrospective morphological analysis of inflammatory infiltrates and do not address causation or provide a clear mechanism for the distinct immune profile.39 Our data cannot provide actuarial or time-dependent analysis of immune cell infiltrates. Another limitation involves study bias inherent to the selection of tumor samples, and the referral pattern of high- and low-grade gliomas treated at our medical center. A final limitation of the study would be the preoperative use of corticosteroids to alleviate mass effect in glioblastoma, whereas no corticosteroid was given preoperatively in the overwhelming majority of patients with pilocytic astrocytoma. While short-term use of corticosteroids may not significantly alter the chronic inflammatory infiltrate profile in the CNS, we cannot entirely exclude a selective effect on our results.

Future studies will need to address the following: 1) the activation of T-cell infiltrates using specific markers; 2) actuarial time-dependent analysis to analyze immune cell infiltrate variations over the development of disease; 3) the molecular profiling of known immunosuppressive pathways of tumor tissue in individual patients;25 and 4) genomic analysis to correlate immunological profiles with genomic and proteomic data. Prospective analysis of immune cell infiltrates and markers may be informative and provide immune profile variations over time that could not be performed in our retrospective analysis.

Conclusions

In this study we present a large comparative analysis of immune cell infiltrates in glioblastoma and pilocytic astrocytoma. By using pilocytic astrocytoma as a relative comparison for glioblastoma and pilocytic astrocytoma, we gain insights into the immune environments of high-grade infiltrative gliomas. Some of our findings will require further analysis in terms of biological significance or causality and raise important questions about the functional status of infiltrating immune CD8-positive T cells. Distinct patterns of intratumoral and perivascular immune cell infiltrates may provide insight into the important role of the tumor microenvironment and the immune response in the pathogenesis of infiltrative gliomas such as glioblastoma.

Disclosure

Dr. Yang was partially supported by an NIH training grant (No. F32 CA132489-01A1), a CNS Dandy Clinical Research Fellowship, and a UCSF Clinical and Translational Scientist Training Research Award in performing this investigation. Dr. Sughrue was partially supported by an NIH training grant (No. F32NS066719-01). Dr. Parsa is partially funded by the Reza and Georgianna Khatib Endowed Chair in Skull Base Tumor Surgery as well as the UCSF Project 5 Specialized Programs of Research Excellence (SPORE) grant (No. 2 P50 CA097257-06).

Author contributions to the study and manuscript preparation include the following. Conception and design: Parsa, Tihan. Acquisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: Parsa, Yang, Sughrue, Tihan. Critically revising the article: all authors. Statistical analysis: all authors. Administrative/technical/material support: Parsa, Yang, Han, Tihan. Study supervision: Parsa, Yang, Tihan.

References

  • 1

    Anderson RCAnderson DEElder JBBrown MDMandigo CEParsa AT: Lack of B7 expression, not human leukocyte antigen expression, facilitates immune evasion by human malignant gliomas. Neurosurgery 60:112911362007

  • 2

    Brenner AVLinet MSFine HAShapiro WRSelker RGBlack PM: History of allergies and autoimmune diseases and risk of brain tumors in adults. Int J Cancer 99:2522592002

  • 3

    Carter DLShieh TMBlosser RLChadwick KRMargolick JBHildreth JEK: CD56 identifies monocytes and not natural killer cells in rhesus macaques. Cytometry 37:41501999

  • 4

    Clark WH JrElder DEGuerry D IVBraitman LETrock BJSchultz D: Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 81:189319041989

  • 5

    Clemente CGMihm MC JrBufalino RZurrida SCollini PCascinelli N: Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77:130313101996

  • 6

    Curiel TJCoukos GZou LAlvarez XCheng PMottram P: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:9429492004

  • 7

    Dunn GPDunn IFCurry WT: Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human glioma. Cancer Immun 7:122007

  • 8

    Dunn GPOld LJSchreiber RD: The three Es of cancer immunoediting. Annu Rev Immunol 22:3293602004

  • 9

    Farmer JPAntel JPFreedman MCashman NRRode HVillemure JG: Characterization of lymphoid cells isolated from human gliomas. J Neurosurg 71:5285331989

  • 10

    Galon JCostes ASanchez-Cabo FKirilovsky AMlecnik BLagorce-Pagès C: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:196019642006

  • 11

    Gervasoni CRidolfo ALRocca AVago Ld'Arminio Monforte A: Cerebral astrocytoma in HIV-infected patients. AIDS 9:4034041995

  • 12

    Graf MRSauer JTMerchant RE: Tumor infiltration by myeloid suppressor cells in response to T cell activation in rat gliomas. J Neurooncol 73:29362005

  • 13

    Hitchcock ERMorris CS: Mononuclear cell infiltration in central portions of human astrocytomas. J Neurosurg 68:4324371988

  • 14

    Holness CLSimmons DL: Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins. Blood 81:160716131993

  • 15

    Jian BYang IParsa AT: Monitoring immune responses after glioma vaccine immunotherapy. Neurosurg Clin N Am 21:1951992010

  • 16

    Liau LMBlack KLMartin NASykes SNBronstein JMJouben-Steele L: Treatment of a patient by vaccination with autologous dendritic cells pulsed with allogeneic major histocompatibility complex class I–matched tumor peptides. Case report. Neurosurg Focus 9:6e82000

  • 17

    Liau LMPrins RMKiertscher SMOdesa SKKremen TJGiovannone AJ: Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res 11:551555252005

  • 18

    Louis DNOhgaki HWiestler ODCavenee WK: WHO Classification of Tumours of the Central Nervous System LyonIARC Press2007

  • 19

    Mihm MC JrClemente CGCascinelli N: Tumor infiltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response. Lab Invest 74:43471996

  • 20

    Moulignier AMikol JPialoux GEliaszewicz MThurel CThiebaut JB: Cerebral glial tumors and human immunodeficiency virus-1 infection. More than a coincidental association. Cancer 74:6866921994

  • 21

    Naito YSaito KShiiba KOhuchi ASaigenji KNagura H: CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:349134941998

  • 22

    Neal JWLlewelyn MBMorrison HLJasani BBorysiewicz LK: A malignant astrocytoma in a patient with AIDS: a possible association between astrocytomas and HIV infection. J Infect 33:1591621996

  • 23

    Ohtani H: Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun 7:42007

  • 24

    Pagès FBerger ACamus MSanchez-Cabo FCostes AMolidor R: Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:265426662005

  • 25

    Parsa ATWaldron JSPanner ACrane CAParney IFBarry JJ: Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13:84882007

  • 26

    Prins RMLiau LM: Immunology and immunotherapy in neurosurgical disease. Neurosurgery 53:1441532003

  • 27

    Ridley ACavanagh JB: Lymphocytic infiltration in gliomas: evidence of possible host resistance. Brain 94:1171241971

  • 28

    Sato EOlson SHAhn JBundy BNishikawa HQian F: Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 102:18538185432005

  • 29

    Schiff DO'Neill BWijdicks EAntin JHWen PY: Gliomas arising in organ transplant recipients: an unrecognized complication of transplantation?. Neurology 57:148614882001

  • 30

    Stevens AKlöter IRoggendorf W: Inflammatory infiltrates and natural killer cell presence in human brain tumors. Cancer 61:7387431988

  • 31

    Sughrue MEYang IHan SJAranda DKane AJAmoils M: Non-audiofacial morbidity after Gamma Knife surgery for vestibular schwannoma. Neurosurg Focus 27:6E42009

  • 32

    Takeuchi JBarnard RO: Perivascular lymphocytic cuffing in astrocytomas. Acta Neuropathol 35:2652711976

  • 33

    von Hanwehr RIHofman FMTaylor CRApuzzo ML: Mononuclear lymphoid populations infiltrating the microenvironment of primary CNS tumors. Characterization of cell subsets with monoclonal antibodies. J Neurosurg 60:113811471984

  • 34

    Wiemels JLWiencke JKSison JDMiike RMcMillan AWrensch M: History of allergies among adults with glioma and controls. Int J Cancer 98:6096152002

  • 35

    Willis SNMallozzi SSRodig SJCronk KMMcArdel SLCaron T: The microenvironment of germ cell tumors harbors a prominent antigen-driven humoral response. J Immunol 182:331033172009

  • 36

    Yang IAghi MK: New advances that enable identification of glioblastoma recurrence. Nat Rev Clin Oncol 6:6486572009

  • 37

    Yang IHan SJKaur GCrane CParsa AT: The role of microglia in central nervous system immunity and glioma immunology. J Clin Neurosci 17:6102010

  • 38

    Yang IHuh NGSmith ZAHan SJParsa AT: Distinguishing glioma recurrence from treatment effect after radiochemotherapy and immunotherapy. Neurosurg Clin N Am 21:1811862010

  • 39

    Yang IKremen TJGiovannone AJPaik EOdesa SKPrins RM: Modulation of major histocompatibility complex Class I molecules and major histocompatibility complex-bound immunogenic peptides induced by interferon-alpha and interferon-gamma treatment of human glioblastoma multiforme. J Neurosurg 100:3103192004

  • 40

    Zhang LConejo-Garcia JRKatsaros DGimotty PAMassobrio MRegnani G: Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:2032132003

Article Information

Address correspondence to: Andrew T. Parsa, M.D., Ph.D., Department of Neurological Surgery, University of California, San Francisco, 400 Parnassus Avenue, A808, San Francisco, California 94143-0350. email: parsaa@neurosurg.ucsf.edu.

Please include this information when citing this paper: published online June 10, 2011; DOI: 10.3171/2011.4.JNS101172.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Summary data of semiquantitative analysis of immunohistochemistry for inflammatory markers in high-grade glioblastoma.

  • View in gallery

    Summary data of semiquantitative analysis of immunohistochemistry for inflammatory markers in low-grade pilocytic astrocytoma.

  • View in gallery

    Photomicrographs demonstrating the scoring classification for rare (A), intermediate (B), and extensive (C) inflammatory infiltrates for intratumoral CD68 in glioblastoma. Original magnification × 20.

  • View in gallery

    Representative photomicrographs for various inflammatory cell markers as indicated in pilocytic astrocytoma. This is a representative staining of different antigens for the pilocytic astrocytoma group demonstrating the different markers of immune cell infiltrate that were analyzed in the low-grade pilocytic astrocytomas. Original magnification × 20.

  • View in gallery

    Bar graph of CD8 and CD68 immunohistochemistry demonstrating the inflammatory infiltrate differences in intratumoral and perivascular immune cell infiltrate in glioblastoma.

References

1

Anderson RCAnderson DEElder JBBrown MDMandigo CEParsa AT: Lack of B7 expression, not human leukocyte antigen expression, facilitates immune evasion by human malignant gliomas. Neurosurgery 60:112911362007

2

Brenner AVLinet MSFine HAShapiro WRSelker RGBlack PM: History of allergies and autoimmune diseases and risk of brain tumors in adults. Int J Cancer 99:2522592002

3

Carter DLShieh TMBlosser RLChadwick KRMargolick JBHildreth JEK: CD56 identifies monocytes and not natural killer cells in rhesus macaques. Cytometry 37:41501999

4

Clark WH JrElder DEGuerry D IVBraitman LETrock BJSchultz D: Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 81:189319041989

5

Clemente CGMihm MC JrBufalino RZurrida SCollini PCascinelli N: Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77:130313101996

6

Curiel TJCoukos GZou LAlvarez XCheng PMottram P: Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:9429492004

7

Dunn GPDunn IFCurry WT: Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human glioma. Cancer Immun 7:122007

8

Dunn GPOld LJSchreiber RD: The three Es of cancer immunoediting. Annu Rev Immunol 22:3293602004

9

Farmer JPAntel JPFreedman MCashman NRRode HVillemure JG: Characterization of lymphoid cells isolated from human gliomas. J Neurosurg 71:5285331989

10

Galon JCostes ASanchez-Cabo FKirilovsky AMlecnik BLagorce-Pagès C: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:196019642006

11

Gervasoni CRidolfo ALRocca AVago Ld'Arminio Monforte A: Cerebral astrocytoma in HIV-infected patients. AIDS 9:4034041995

12

Graf MRSauer JTMerchant RE: Tumor infiltration by myeloid suppressor cells in response to T cell activation in rat gliomas. J Neurooncol 73:29362005

13

Hitchcock ERMorris CS: Mononuclear cell infiltration in central portions of human astrocytomas. J Neurosurg 68:4324371988

14

Holness CLSimmons DL: Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins. Blood 81:160716131993

15

Jian BYang IParsa AT: Monitoring immune responses after glioma vaccine immunotherapy. Neurosurg Clin N Am 21:1951992010

16

Liau LMBlack KLMartin NASykes SNBronstein JMJouben-Steele L: Treatment of a patient by vaccination with autologous dendritic cells pulsed with allogeneic major histocompatibility complex class I–matched tumor peptides. Case report. Neurosurg Focus 9:6e82000

17

Liau LMPrins RMKiertscher SMOdesa SKKremen TJGiovannone AJ: Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res 11:551555252005

18

Louis DNOhgaki HWiestler ODCavenee WK: WHO Classification of Tumours of the Central Nervous System LyonIARC Press2007

19

Mihm MC JrClemente CGCascinelli N: Tumor infiltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response. Lab Invest 74:43471996

20

Moulignier AMikol JPialoux GEliaszewicz MThurel CThiebaut JB: Cerebral glial tumors and human immunodeficiency virus-1 infection. More than a coincidental association. Cancer 74:6866921994

21

Naito YSaito KShiiba KOhuchi ASaigenji KNagura H: CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:349134941998

22

Neal JWLlewelyn MBMorrison HLJasani BBorysiewicz LK: A malignant astrocytoma in a patient with AIDS: a possible association between astrocytomas and HIV infection. J Infect 33:1591621996

23

Ohtani H: Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun 7:42007

24

Pagès FBerger ACamus MSanchez-Cabo FCostes AMolidor R: Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:265426662005

25

Parsa ATWaldron JSPanner ACrane CAParney IFBarry JJ: Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13:84882007

26

Prins RMLiau LM: Immunology and immunotherapy in neurosurgical disease. Neurosurgery 53:1441532003

27

Ridley ACavanagh JB: Lymphocytic infiltration in gliomas: evidence of possible host resistance. Brain 94:1171241971

28

Sato EOlson SHAhn JBundy BNishikawa HQian F: Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 102:18538185432005

29

Schiff DO'Neill BWijdicks EAntin JHWen PY: Gliomas arising in organ transplant recipients: an unrecognized complication of transplantation?. Neurology 57:148614882001

30

Stevens AKlöter IRoggendorf W: Inflammatory infiltrates and natural killer cell presence in human brain tumors. Cancer 61:7387431988

31

Sughrue MEYang IHan SJAranda DKane AJAmoils M: Non-audiofacial morbidity after Gamma Knife surgery for vestibular schwannoma. Neurosurg Focus 27:6E42009

32

Takeuchi JBarnard RO: Perivascular lymphocytic cuffing in astrocytomas. Acta Neuropathol 35:2652711976

33

von Hanwehr RIHofman FMTaylor CRApuzzo ML: Mononuclear lymphoid populations infiltrating the microenvironment of primary CNS tumors. Characterization of cell subsets with monoclonal antibodies. J Neurosurg 60:113811471984

34

Wiemels JLWiencke JKSison JDMiike RMcMillan AWrensch M: History of allergies among adults with glioma and controls. Int J Cancer 98:6096152002

35

Willis SNMallozzi SSRodig SJCronk KMMcArdel SLCaron T: The microenvironment of germ cell tumors harbors a prominent antigen-driven humoral response. J Immunol 182:331033172009

36

Yang IAghi MK: New advances that enable identification of glioblastoma recurrence. Nat Rev Clin Oncol 6:6486572009

37

Yang IHan SJKaur GCrane CParsa AT: The role of microglia in central nervous system immunity and glioma immunology. J Clin Neurosci 17:6102010

38

Yang IHuh NGSmith ZAHan SJParsa AT: Distinguishing glioma recurrence from treatment effect after radiochemotherapy and immunotherapy. Neurosurg Clin N Am 21:1811862010

39

Yang IKremen TJGiovannone AJPaik EOdesa SKPrins RM: Modulation of major histocompatibility complex Class I molecules and major histocompatibility complex-bound immunogenic peptides induced by interferon-alpha and interferon-gamma treatment of human glioblastoma multiforme. J Neurosurg 100:3103192004

40

Zhang LConejo-Garcia JRKatsaros DGimotty PAMassobrio MRegnani G: Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:2032132003

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 5 5 5
Full Text Views 125 125 50
PDF Downloads 76 76 46
EPUB Downloads 0 0 0

PubMed

Google Scholar