α_Lβ₂ Integrin is indispensable for CD8⁺ T‐cell recruitment in experimental pancreatic and hepatocellular cancer

Abstract

Recruitment of activated leukocytes from peripheral blood into the tumor tissue is a crucial step of the immune response, which is controlled by the interaction between specific adhesion molecules such as endothelial ICAM-1 and leukocyte b 2 -integrins. Although attenuated expression of adhesion molecules on tumor endothelium has been proposed to represent a mechanism, which suppresses the intratumoral leukocyte infiltration, the relevance of adhesion molecules for leukocyte recruitment in tumor tissue is poorly understood. The present study is the first investigation of the role of ICAM-1 and b 2 -integrins in leukocyte recruitment in pancreatic and hepatocellular cancer in vivo, which was studied using knockout mice, intravital time-lapse microscopy and immunohistochemistry. We found that tumor tissue of both pancreatic and hepatocellular cancer was infiltrated with numerous active lymphoid and myeloid leukocytes, although the leukocyte extravasation rate in tumor blood vessels was very low. The knockout of LFA-1 (also known as a L b 2 integrin) strongly suppressed recruitment of CD8 1 T cells whereas no significant differences of leukocyte adhesion and infiltration were found in ICAM-1 2/2 and Mac-1mice. Analysis of the interstitial leukocyte migration demonstrated that intratumoral leukocytes used haptokinetic type of migration, however, no significant differences of leukocyte migration between any knockout strains were found. We concluded that leukocyte recruitment in pancreatic and hepatocellular cancer is a slow-going process whose dynamics clearly contrasts to a high-speed leukocyte recruitment during acute inflammation. In contrast to acute inflammatory reaction, only LFA-1 controls recruitment of CD8 1 T-cells in both pancreatic and hepatocellular cancer, whereas ICAM-1 and Mac-1 are dispensable.Pancreatic and hepatocellular cancer remain an extremely aggressive malignancies with a poor prognosis. 1 The mean 5-year survival is 6% and 14% for pancreatic and liver cancer, respectively.

Role of liver ICAM-1 in metastasis

“…Several adhesion molecules, such as E-selectin, vascular cellular adhesion molecule (VCAM)-1 and ICAM-1, exhibit increased expression in the liver during metastatic invasion (22). Among them, ICAM-1 mediates several stages of the metastatic cascade, including the adhesion of tumor cells to the endothelial wall (23)(24)(25), endothelial cell activation of pro-metastatic signaling pathways (26)(27)(28), tumor cell extravasation (23,29), the recruitment of immune cell populations (28,30,31), the pro-angiogenic response (32) and the transdifferentiation of stellate cells during the desmoplastic response (33,34). This review will focus on the role of ICAM-1 during the different events of the metastatic cascade that drives colonization of the liver by circulating tumor cells, and how it modulates the liver microenvironment to facilitate metastasis.…”

Integrin α4 is involved in the regulation of glioma-induced motility of bone marrow mesenchymal stem cells

“…Recent findings demonstrated that integrins are involved in the regulation of cell migration, such as lymphocytes infiltration in inflammation and tumors (11,12). Integrin α4 is a subunit of vascular cell adhesion molecule-1 (VCAM-1) receptor, very late antigen-4 (VLA-4).…”

Pancreatic Cancer Fostered Immunosuppression Privileges Tumor Growth and Progression

“…The adhesion molecule L1CAM (CD171), which increases during PDAC progression in the ductal epithelium [111], also appears to be involved in reducing CD4 + T cell proliferation and in inducing CD69 expression, probably because it mediates the release of soluble factors promoting the generation of CD4 + T cells with a CD69 + phenotype [105]. Another PDAC-associated adhesion molecule, an ICAM-1 receptor α L β 2 integrin (also known as LFA-1 or CD11a/CD18), regulates CD8 + T cell recruitment: only its knockout results in a marked impairment of CD8 + T cell infiltration in experimental pancreatic tumors in mice, probably because its lack of expression impairs T cells activation and differentiation [112]. Overexpression and secretion by activated PSCs of β-galactoside-binding protein Galectin-1 (Gal-1), another molecule that mediates immunosuppression in PDAC by targeting T cell, increases Th2 and decreases Th1 cytokines, inducing CD4 + and CD8 + T cell apoptosis [113].…”