2 research outputs found
ICAM-1-LFA-1 dependent CD8+ T-Lymphocyte aggregation in tumor tissue prevents recirculation to draining lymph nodes
The quantity of T-lymphocytes reaching the draining lymph nodes from tumors is likely
important to mount effective distant responses and for the establishment of long term
systemic memory. Looking into mechanisms behind lymphocyte egress, we directed
our attention to leukocyte adhesion mechanisms inside tumors. Here we demonstrate
that activated T-cells form intra-tumor aggregates in a LFA-1-ICAM-1-dependent fashion
in mouse models of melanoma and breast cancer. We also provide evidence of the
presence of T-cell clusters in primary human melanoma. Disruption of LFA-1-ICAM-1
interactions, and thereby T-cell clustering, enhances the arrival of activated CD8+
T-cells to tumor draining lymph nodes in both transplanted and spontaneous cancer
models. Interestingly, upon ICAM-1 blockade, the expression of the chemotactic
receptor CCR7 augments in tumor infiltrating lymphocytes and in in-vitro de-clustered
T cells, as well as their ability to transmigrate across lymphatic endothelial cells. We
propose that ICAM-1-mediated homotypic T-lymphocyte aggregation may serve as a
tumor-mediated immune retention mechanism entrapping activated CD8+ T cells in
the tumor microenvironment. Modulation of T-cell adhesion may be of use to improve
the transit of activated lymphocytes toward the lymph nodes and their subsequent
recirculation
Intercellular adhesion molecule-1 and vascular cell adhesion molecule are induced by ionizing radiation on lymphatic endothelium
Purpose/Objectives
The goal of this study was to assess the effects of ionizing radiation on the expression of the integrin ligands ICAM-1 and VCAM that control leucocyte transit by lymphatic endothelial cells.
Materials/Methods
Confluent monolayers of primary human lymphatic endothelial cells (LEC) were irradiated with single dose of 2, 5, 10 or 20 Gy, with 6 MeV-x-rays using a Linear-Accelerator. ICAM-1 and VCAM expression was determined by flow cytometry. Human tissue specimens received a single dose of 20 Gy with 15 MeV-x-rays. MC38, B16-OVA or B16-VEGF-C tumors grown in C57BL/6 mice were irradiated with single dose of 20Gy using a Linear-Accelerator fitted with a 10mm Radiosurgery collimator. Clinical samples were obtained from patients previous and 4 weeks after complete standard radiotherapy. ICAM-1 and VCAM expression was detected in all tissue specimens by confocal microscopy. To understand the role of TGFβ in this process anti-TGFβ blocking mAb were injected i.p. 30min before radiotherapy. Cell adhesion to irradiated LEC was analyzed in adhesion experiments performed in the presence or in the absence of anti- TGFβ and /or anti-ICAM1 blocking mAb.
Results
We demonstrate that lymphatic endothelial cells in tumor samples experience induction of surface ICAM-1 and VCAM when exposed to ionizing radiation in a dose- and time-dependent manner. These effects can be recapitulated in cultured LEC, and are in part mediated by TGFβ. These data are consistent with increases in ICAM-1 and VCAM expression on LYVE-1+ endothelial cells in freshly explanted human tumor tissue and in mouse transplanted tumors after radiotherapy. Finally, ICAM-1 and VCAM expression accounts for enhanced adherence of human T lymphocytes to irradiated LEC.
Conclusion
Our results show induction of ICAM-1 and VCAM on LVs in irradiated lesions and offer a starting point for elucidating the biological and therapeutic implications of targeting leukocyte traffic in combination to immunotherapy