Perivascular leukocyte aggregates form in tumors after chemotherapy.
Location
Georgia
Start Date
12-5-2015 1:00 PM
Description
Background: Evidence is mounting to support the hypothesis that immune processes play a critical role in tumor clearance after standard treatments such as chemotherapy. In spite of this, anti-tumor immunity is often less robust than expected. One of the major problems with immunologic therapy for tumors is that immune cells fail to traffic to the tumor and often cannot cross the vascular endothelium to enter the tumor parenchyma. Objective: To test the hypothesis that standard chemotherapy treatment leads to immune activation. Design/Methods: We used syngeneic murine tumor models of glioblastoma (intracranial orthotopic GL261 implantation) and melanoma (subcutaneous B16F10 implantation) to study the effect of chemotherapy (temozolomide or cyclophosphamide) on immune cells within the tumors. Results: In both glioblastoma and melanoma, leukocytes aggregated in perivascular locations after chemotherapy. These perivascular immune cell “cuffs” became more prominent and frequent over time, but were confined to the tumor and peritumoral tissue. Despite the proximity to intratumoral vascular structures, analysis of endothelial integrin expression showed no upregulation of cell-surface ICAM or VCAM after chemotherapy. Immunohistochemical analysis showed a preponderance of macrophage lineage cells with a less prominent CD4 T cell component, and very few CD8 T cells. Only a very small number of T cells were in cell cycle by Ki67 staining, and a high proportion of the CD4 T cells were found to be regulatory T cells. When tumor-specific CD8 T cells were transferred into tumor-bearing mice, they did not traffic to the tumors. Finally, perivascular cuffs failed to form in Rag1-deficient host mice that lack T cells. Conclusions: Our data demonstrate that chemotherapy treatment results in large immune cell aggregates around tumor vessels which are composed primarily of macrophage-lineage cells. Despite these prominent perivascular leukocyte cuffs, the vascular endothelium failed to demonstrate an activated phenotype. Interestingly, T cells were mechanistically critical for cuff formation, even though they were less frequent in the cuff architecture. Based on the histiocytic nature of the perivascular cuffs, we speculate that they are made up of tumor-associated macrophages/microglia that sense tumor tissue damage and migrate to perivascular locations, where they can protect the tumor from immune attack.
Perivascular leukocyte aggregates form in tumors after chemotherapy.
Georgia
Background: Evidence is mounting to support the hypothesis that immune processes play a critical role in tumor clearance after standard treatments such as chemotherapy. In spite of this, anti-tumor immunity is often less robust than expected. One of the major problems with immunologic therapy for tumors is that immune cells fail to traffic to the tumor and often cannot cross the vascular endothelium to enter the tumor parenchyma. Objective: To test the hypothesis that standard chemotherapy treatment leads to immune activation. Design/Methods: We used syngeneic murine tumor models of glioblastoma (intracranial orthotopic GL261 implantation) and melanoma (subcutaneous B16F10 implantation) to study the effect of chemotherapy (temozolomide or cyclophosphamide) on immune cells within the tumors. Results: In both glioblastoma and melanoma, leukocytes aggregated in perivascular locations after chemotherapy. These perivascular immune cell “cuffs” became more prominent and frequent over time, but were confined to the tumor and peritumoral tissue. Despite the proximity to intratumoral vascular structures, analysis of endothelial integrin expression showed no upregulation of cell-surface ICAM or VCAM after chemotherapy. Immunohistochemical analysis showed a preponderance of macrophage lineage cells with a less prominent CD4 T cell component, and very few CD8 T cells. Only a very small number of T cells were in cell cycle by Ki67 staining, and a high proportion of the CD4 T cells were found to be regulatory T cells. When tumor-specific CD8 T cells were transferred into tumor-bearing mice, they did not traffic to the tumors. Finally, perivascular cuffs failed to form in Rag1-deficient host mice that lack T cells. Conclusions: Our data demonstrate that chemotherapy treatment results in large immune cell aggregates around tumor vessels which are composed primarily of macrophage-lineage cells. Despite these prominent perivascular leukocyte cuffs, the vascular endothelium failed to demonstrate an activated phenotype. Interestingly, T cells were mechanistically critical for cuff formation, even though they were less frequent in the cuff architecture. Based on the histiocytic nature of the perivascular cuffs, we speculate that they are made up of tumor-associated macrophages/microglia that sense tumor tissue damage and migrate to perivascular locations, where they can protect the tumor from immune attack.