Immune cell infiltrate differences in pilocytic astrocytoma and glioblastoma: Evidence of distinct immunological microenvironments that reflect tumor biology: Laboratory investigation
Department of Neurosurgery, University of California, Los Angeles, California, USA. Journal of Neurosurgery
(Impact Factor: 3.74).
06/2011; 115(3):505-11. DOI: 10.3171/2011.4.JNS101172
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.
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 mm(2)). 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.
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.
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.
Available from: ncbi.nlm.nih.gov
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ABSTRACT: In metronomic chemotherapy, frequent drug administration at lower than maximally tolerated doses can improve activity while reducing the dose-limiting toxicity of conventional dosing schedules. Although the antitumor activity produced by metronomic chemotherapy is attributed widely to antiangiogenesis, the significance of this mechanism remains somewhat unclear. In this study, we show that a 6-day repeating metronomic schedule of cyclophosphamide administration activates a potent antitumor immune response associated with brain tumor recruitment of natural killer (NK) cells, macrophages, and dendritic cells that leads to marked tumor regression. Tumor regression was blocked in nonobese diabetic/severe combined immunodeficient (NOD/SCID-γ) mice, which are deficient or dysfunctional in all these immune cell types. Furthermore, regression was blunted by NK cell depletion in immunocompetent syngeneic mice or in perforin-deficient mice, which are compromised for NK, NKT, and T-cell cytolytic functions. Unexpectedly, we found that VEGF receptor inhibitors blocked both innate immune cell recruitment and the associated tumor regression response. Cyclophosphamide administered at a maximum tolerated dose activated a transient, weak innate immune response, arguing that persistent drug-induced cytotoxic damage or associated cytokine and chemokine responses are required for effective innate immunity-based tumor regression. Together, our results reveal an innate immunity-based mechanism of tumor regression that can be activated by a traditional cytotoxic chemotherapy administered on a metronomic schedule. These findings suggest the need to carefully evaluate the clinical effects of combination chemotherapies that incorporate antiangiogenesis drugs targeting VEGF receptor.
Cancer Research 03/2012; 72(5):1103-15. DOI:10.1158/0008-5472.CAN-11-3380 · 9.33 Impact Factor
Available from: Cees van Kooten
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Allogeneic islets of Langerhans transplantation is hampered in its success as a curative treatment of type 1 diabetes by the absence of potent, specific, and nontoxic immunosuppressive drugs. Here, we assessed whether donor bone marrow-derived dexamethasone-treated dendritic cells (dexDCs) could prolong islet allograft survival in a full major histocompatibility complex mismatch rat model.
Rodent allogeneic islet transplantation was performed from DA rats to Lewis rats and vice versa. Permanently immature dendritic cells were generated from the bone marrow of DA and Lewis rats by treatment with dexamethasone. Animals were either vehicle or donor dexDCs pretreated. Serum was used to monitor glucose, C-peptide, and alloreactive antibodies.
The transplantation of DA islets into Lewis recipients showed direct graft failure with reduced numbers of β-cells when rats were pretreated with donor dexDCs. In the reverse model (Lewis islets into DA recipients), dexDC-treated DA recipients even showed a significantly accelerated rejection of Lewis islets. Immunohistochemical analysis of allograft tissue of dexDC-treated recipients showed a predominant natural killer cell infiltration and a presence of antibody reactivity in the absence of complement deposition. Alloreactive antibodies were solely found in dexDC-treated recipients.
Our study shows that pretreatment with donor-derived dexDCs induces an antibody-mediated rejection in this islet transplantation rodent model.
Transplantation 10/2012; 94(9). DOI:10.1097/TP.0b013e31826acd01 · 3.83 Impact Factor
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ABSTRACT: Pathologists and immunologists have collaborated over many years in their efforts to understand and properly diagnose cancer. The ability of pathologists to correctly diagnose this disease was facilitated by the development of immunohistology that utilized specificity of antibodies to distinguish between normal cells and cancer cells. Further boost was provided through the advent of monoclonal antibodies. The two disciplines are now together on the brink of a paradigm shift resulting from a better understanding of the importance for cancer diagnosis and prognosis to consider not only the characteristics of the cancer cells, but also the cancer microenvironment reflecting the host response to the disease. This new immunology and pathology alliance named “Immunoscore” will advance research in both disciplines as well as benefit patients.
Experimental and Molecular Pathology 12/2012; 93(3):315–318. DOI:10.1016/j.yexmp.2012.10.013 · 2.71 Impact Factor
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